• 17 Jan 2020 12:03 PM | Anonymous

    Authors: Kathryn M. Holt, PharmD, BCPS, University of Missouri-Kansas City School of Pharmacy, Clinical Assistant Professor Meritas Health North Kansas City

    Amanda M. Stahnke, PharmD, BCACP, University of Missouri-Kansas City School of Pharmacy, Clinical Associate Professor Kansas City VA Honor Annex

    Diabetes mellitus remains one of the leading causes of chronic kidney disease (CKD) and occurs in 20-40% of people with diabetes.1 With the continued increase in prevalence of CKD in diabetes, limited pharmacologic therapies exist to assist in decreasing the development and progression outside of renin-angiotensin-aldosterone system (RAAS) agents.1-2 Recent clinical trials with sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) have demonstrated their potential role in this much needed area. SGLT2-Is currently available on the market include canagliflozin, empagliflozin, dapagliflozin, and ertugliflozin. Despite the potentially blunted glucose lowering effect in patients with CKD, several proposed mechanisms regarding renal benefit exist: reduced intraglomerular pressure, renal tubular reabsorption and oxidative renal stress; and improved tubuloglomerular feedback.1-5

    Primary Outcome Data:

    To date only canagliflozin has published primary literature regarding renal outcomes. CREDENCE enrolled 4401 patients and was published in June 2019. The trial included patients 30 years of age or older with type 2 diabetes (T2DM), a hemoglobin A1c (A1c) of 6.5-12%, and CKD (eGFR [estimated glomerular filtration rate] 30-90ml/min/1.73m²) with albuminuria (albumin-to-creatinine ratio [UACR] >300-5000mg/g). Patients were randomized in a 1:1 fashion to receive canagliflozin 100mg PO daily or matching placebo and had to be taking a RAAS agent (angiotensin converting enzyme inhibitor or angiotensin receptor blocker) for at least four weeks prior to entry in to the study. The majority of patients enrolled in the trial were Caucasian (66.6%), had baseline hypertension (HTN) (96.8%), and were male (66.1%). Average age and A1c at baseline were 63 and ~8.3%. An interim analysis resulted in sufficient number of primary outcome events, leading to the early termination of the trial at ~2.6 years. The primary composite outcome of end stage kidney disease (ESRD), including need for dialysis or eGFR <15ml/min/1.73m² for at least 30 days, kidney transplant; doubling of serum creatinine (SrCr) from baseline, and death from cardiovascular (CV) or renal disease occurred in 43.2 and 61.2 events per 1000 patient years in the canagliflozin and placebo groups respectively (HR 0.70, CI 0.59-0.82, P=0.00001, NNT 22). Doubling of SrCr from baseline and development of ESRD were also significantly different between groups (20.7 versus 33.8 events per 1000 patient years, HR 0.60, CI 0.48-0.76, P<0.001 and 20.4 versus 29.4 events per 1000 patient years, HR 0.68, CI 0.54-0.86, P=0.002). There were no statistically significant differences between subgroups in the trial though a trend favoring canagliflozin was seen in patients with lower eGFRs (30-<60ml/min/1.73m2) and higher baseline UACR (>1000mg/g). The results of CREDENCE support that SGLT2-Is may provide renal benefit, specifically in patients at high risk for CKD due to T2DM.6

    Secondary Outcome Data:

    Primary outcome data has yet to be published for the other SGLT2-Is; however, many of the cardiovascular outcomes trials (CVOTs) have included renal endpoints as secondary analyses. The CANVAS Program evaluated the effect of canagliflozin on the secondary outcome of progression of albuminuria (30% increase or change from normo- to micro- or micro- to macroalbuminuria) and included an exploratory composite outcome of need for dialysis or transplant, death from renal disease, and sustained 40% reduction in eGFR. Both the secondary and exploratory outcomes occurred less often in patients receiving canagliflozin versus placebo (HR 0.73, CI 0.67-0.79 for progression of albuminuria and HR 0.6, CI 0.47-0.77 for composite renal outcome), but due to sequential hypothesis testing and failure of the first secondary endpoint to meet statistical significance, statistical analysis was not completed on the renal secondary outcome.7

    EMPA-REG OUTCOME assessed the impact of empagliflozin versus placebo on composite microvascular outcomes, which included incident or worsening nephropathy (progression to macroalbuminuria, doubling of SrCr with an eGFR ≤45ml/min/1.73m², initiation of renal replacement therapy or death from renal cause). The occurrence of nephropathy was lower in the empagliflozin group versus placebo (12.7 versus 18.8%, HR 0.61, CI 0.53-0.7, P<0.001). Additionally, all individual composite renal outcomes were found to be statistically significant favoring empagliflozin.5

    DECLARE-TIMI 58, dapagliflozin CVOT, included analysis of new onset ESRD, death from renal or CV causes, and 40% sustained reduction in eGFR as a secondary composite endpoint. A lower incidence of the renal composite endpoint was seen in the dapagliflozin group versus placebo (4.3 versus 5.6%, HR 0.76, CI 0.67-0.87).8

    Secondary outcomes in VERTIS-CV regarding renal effects of ertugliflozin include first event of renal death, dialysis or transplant, along with doubling of SrCr. The trial was expected to end late 2019 and results are pending.9


    Based on CVOT and renal outcomes, The American Diabetes Association (ADA) now recommends SGLT2-Is (preferring agents with supporting data) as second line agents in many patients, including those with atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), CKD, risk for hypoglycemia or those in which weight gain is a concern.2 Though some are rare, adverse drug reactions (ADRs) seen with the use of SGLT2-Is include genital mycotic infections, hypovolemia, hypotension, diabetic ketoacidosis (DKA), Fournier’s gangrene, lower limb amputation and hyperkalemia (canagliflozin).10-13 Acute kidney injury resulting from hypovolemia may be a concern in specific patient populations, such as those taking concomitant diuretics, but recent data did not support this association.6 Consideration to patient specific factors such as past medical history, baseline renal function, risk factors, and patient preference should be taken in to account when deciding to initiate an SGLT2-I.

    SGLT2-Is are an exciting development in the treatment of T2DM and with growing evidence will likely become a mainstay in therapy to assist with decreasing the development and progression of CKD in this patient population. We anxiously await the publication of additional trials discussing the potential renal benefits of SGLT2-Is, including DAPA-CKD, EMPA-KIDNEY, and VERTIS-CV to solidify this important drug class’s place in therapy.

    References:

    1. American Diabetes Association. 11. Microvascular complications and foot care: Standards of Medical Care in Diabetes 2020. Diabetes Care 2020;43(Suppl. 1):S135–S151. https://doi.org/10.2337/dc20-s011
    2. American Diabetes Association. 2. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes 2020. Diabetes Care 2020;43(Suppl. 1):S98–S110. https://doi.org/10.2337/dc20-S009
    3. Alicic RZ, Neumiller JJ, Johnson EJ, Dieter B, Tuttle KR. Sodium-glucose cotransporter 2 inhibition and diabetic kidney disease. Diabetes 2019;68:248-257. https://doi.org/10.2337/dbi18-0007
    4. Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 inhibitors and the diabetic kidney. Diabetes Care 2016;39(Suppl. 2):S165–S171. doi:10.2337/dcS15-3006
    5. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323-334. doi:10.1056/NEJMoa1515920
    6. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–2306. doi:10.1056/NEJMoa1811744
    7. Neal B, Perkovic V, Mahaffey KW, et al.; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–657. doi:10.1056/NEJMoa1611925
    8. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-357. doi: 10.1056/NEJMoa1812389
    9. Cannon CP, McGuire DK, Pratley R, et al. Design and baseline characteristics of the evaluation of ertugliflozin efficacy and safety cardiovascular outcomes trial. Am Heart J 2018;206:11-23. https://doi.org/10.1016/j.ahj.2018.08.016
    10. Invokana [package insert]. Titusville, NJ: Janssen; 2019.
    11. Jardiance [package insert]. Ridgefield, CT: Boehringer Ingelheim; 2018.
    12. Farxiga [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2019.
    13. Steglatro [package insert]. Whitehouse Station, NJ: Merck; 2017.


  • 17 Jan 2020 11:42 AM | Anonymous

    Author: Miriam Chikodili Oguejiofor, Pharm.D

    Learning Objectives:

    1. Understand the issues associated with trough-based vancomycin monitoring
    2. Identify scenarios where AUC-based vancomycin dosing approach may not be necessary
    3. Describe the benefits and limitations of the Bayesian and Equation-based approaches of AUC determination

    Vancomycin is the antibiotic of choice for empiric and definitive treatment of methicillin resistant Staph aureus (MRSA) infection. Despite its introduction over half a century ago, controversies still exist regarding the optimum dosing regimens and pharmacokinetic/pharmacodynamic properties of vancomycin.1 Vancomycin drug monitoring continues to be a focus of pharmacists working both inpatient and at outpatient infusion centers due to its wide interpatient and intrapatient pharmacokinetic variability and vancomycin-induced nephrotoxicity (VIN). The therapeutic targets of vancomycin have evolved over time. The ratio of the 24-hour area under the concentration-time curve (AUC24) to the minimum inhibitory concentration (MIC) best characterizes the effectiveness of vancomycin as initially demonstrated by an experimental murine infection model.2

    Moise-Broder and colleagues provided the first clinical evidence supporting AUC as a therapeutic target. They demonstrated improved time to pathogen eradication in patients with S. aureus pneumonia who achieved an AUC:MIC of at least 350 mg.hr/L.3 Subsequently, increasing data have been published supporting the AUC:MIC as the therapeutic target associated with improved outcomes. However, a trough targeted approach has been used for vancomycin monitoring due to a perceived difficulty associated with determining vancomycin AUC values in “real time” and a lack of clearly defined AUC:MIC targets.1,4

    In 2009, the Infectious Disease Society of American, American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists published a consensus guideline on the therapeutic monitoring of vancomycin in adults. It was suggested that monitoring of pre-dose trough concentrations is “the most accurate and practical method for monitoring efficacy” and that the optimally timed sample should be obtained under steady state conditions in adults with normal renal function. The guideline abandoned the measurement of peak vancomycin concentrations with the rationale that there was no data correlating such peak concentration with either efficacy or vancomycin-associated toxicity. The guideline recommended that a ratio of the 24-hour area under the concentration-time curve (AUC0-24) to the MIC (AUC/MIC ratio) that is ≥ 400 times the MIC for the organism should be targeted for clinical effectiveness. The committee asserted that vancomycin trough concentration is a good surrogate for the AUC in adults with normal renal function (CrCl ≥ 100 ml/min). It was also recommended that vancomycin trough be maintained above 10 mcg/ml for all infections and a goal of 15 to 20 mcg/ml should be targeted for complicated infections such as bacteremia, osteomyelitis, endocarditis, meningitis and S. aureus (MRSA) pneumonia. This higher trough goal value of 15-20 mcg/ml would correlate with an AUC target of ≥ 400 mg.hr/L when the vancomycin MIC is ≤ 1 mg/L.1, 5-9

    These recommendations have been integrated into clinical practice. However, the clinical benefits of maintaining higher vancomycin trough have not been well-defined.10 In addition, as vancomycin doses are increased in attainment of target trough goal for these complicated infections, so did reported instances of vancomycin-associated nephrotoxicity. Even trough values within the target range of 15-20 mcg/ml are associated with increased incidence of nephrotoxicity relative to troughs < 15 mcg/ml.10-13 The result of the study conducted by Hale et al showed that although patients with trough levels >10 mcg/ml were more likely to achieve the pharmacodynamic AUC24:MIC target than those with trough levels < 10 mcg/ml, there was no statistically significant increase in AUC24:MIC target attainment with trough levels > 15 mcg/ml. The study also showed that patients who developed VIN had a mean trough of 19.5 mcg/ml compared to 14.5 mcg/ml in patients who did not. Thus, targeting a higher trough goal increased the risk of toxicity but did not increase the proportion of patients achieving the pharmacodynamic target.14

    Using a 5,000-patient Monte Carlo simulation, Neely and colleagues estimated that about 60% of patients could achieve therapeutic AUC values with trough concentration of < 15 mcg/ml assuming a vancomycin MIC value of ≤ 1 mcg/ml. They support a reassessment of target serum levels of vancomycin given the aggressive trough concentrations (>15 mcg/ml) may not be necessary to achieve the desired AUC targets.2,5

    Presently, a distinct threshold for toxic AUC exposure is undefined; however, an AUC based vancomycin dosing approach may be preferred to a trough-based approach due to potential benefits of safety and effectiveness. It is important for institutions to consider scenarios where AUC-based dosing might not be necessary prior to its implementation. A controversial scenario is for the treatment of meningitis or CNS infections. While the guidelines (strong recommendation, low quality evidence) support target trough of 15-20 mcg/ml, recent studies have emerged demonstrating increased toxicity associated with higher troughs. Thus, institutions must weigh the risk and benefits of targeting troughs over AUC. Another scenario where institutions can possibly avoid AUC-based dosing is in patients receiving renal replacement therapy in whom the duration of dialysis session and timing inconsistency can lead to unpredictable vancomycin elimination rate. Also, in patients with acute kidney injury, it is difficult to predict a standard maintenance dose due to unpredictable vancomycin clearance. Hence trough-based dosing as well as dosing by level is a better approach in these patients. However, AUC-based strategy should be initiated once renal function stabilizes. Of note, patients with stable chronic kidney disease (CKD) who are not receiving renal replacement therapy should be appropriate candidates for AUC-based dosing. In patients receiving vancomycin for surgical prophylaxis, AUC-based dosing strategy might be unnecessary since the anticipated duration of vancomycin therapy is short and routine serum concentration monitoring will not affect patients’ outcomes. Furthermore, some institutions may choose to exclude skin and soft tissue infections (in the absence of hemodynamic instability and/or bacteremia) as clinical trials support the standard weight-based vancomycin dosing without a need for any monitoring for short-course therapy.2

    Vancomycin AUC can be determined using a Bayesian approach or an equation-based methodology such as trapezoidal model or first order equation. The Bayesian method is based on Bayes’ Theorem - “a theorem of conditional probabilities that describes how evidence from previous experiences and the likelihood of separate events are related”. First it provides estimates of an individual patient’s pharmacokinetic (PK) parameters such as volume of distribution, clearance prior to vancomycin administration based on the way the drug behaved in prior patient population that received vancomycin (the Bayesian prior). Secondly, after a given drug regimen and obtaining a single level from a patient, a revision of the pharmacokinetic estimates is provided. This estimate known as the Bayesian conditional posterior can be used to estimate a patient’s specific AUC. There are several advantages of the Bayesian approach over the traditional first-order equation method: i) Vancomycin concentrations can be obtained at any time, even over different dosing intervals. ii) Sample collection is not limited to trough and samples do not necessarily have to be taken under steady-state conditions. iii) It is an adaptive program as samples collected within the first 24-48 hours and the information obtained are used to influence subsequent dosing. iv) It accounts for the pathophysiological changes that readily occur in patients especially in critically ill patients by including covariates such as creatinine clearance in the PK models. These covariates which represent the dynamic changes are used to identify dosing schemes and predict future dosing in a patient whose PK profile is evolving. However, further studies on the incorporation of these covariates are required. A primary limitation of the Bayesian approach is the cost of the software which varies in price depending on the program type and the subscription model. Also, the Bayesian approach relies on many assumptions which tend to overestimate the AUC.1,4

    The equation-based approach involves obtaining two levels during the same dosing interval drawn at steady state: a distributional peak (1-2 hours post infusion) and a trough. The levels are used to calculate a patient’s PK parameters which are then incorporated into equations such as trapezoidal formula to calculate a patient’s AUC for a single dose. To determine the AUC 24, the single dose must be multiplied by the number of daily doses administered. The equation-based approach relies on fewer assumptions and provides a” real-world” snapshot of the patient-level information which can be rapidly translated for clinical use. In addition, it does not require the purchase of a special software. Limitation of the equation-based model include sampling must be done at steady state since it only provides a snapshot of the AUC for the sampling period and cannot account for potential changes in AUC due to continuing physiologic changes. There is a possibility that the AUC may be slightly underestimated since it is unable to account for the entirety of the administrative and distributive phases. A key issue to consider when applying the equation-based approach is the optimal sampling window for collection of peaks as samples if collected too early lead to flawed results. However, the equation-based approach is a viable option for smaller hospitals and other institutions with cost concerns. Generally, the equation-based approach has been validated to have similar accuracy and bias as the Bayesian approach.1,4

    In this modern era where individualized therapies are recognized, a one-size-fits-all approach to drug dose delivery may no longer be appropriate. Implementation of the AUC:MIC based vancomycin dosing is aimed at optimizing patient outcomes and minimizing toxicity. However, it presents a new challenge to pharmacists who will work towards educating themselves and other healthcare professionals about this change. With the anticipated transition in vancomycin dosing to AUC, hospitals and healthcare institutions must consider the pros and cons and decide which approach best meets the needs of both their institutions and their patients.

    References

    1. Stevens R, Balmes, F. Use AUC to optimize vancomycin dosing. Pharmacy Times. https://www.pharmacytimes.com/publications/health-system edition/2019/march2019/use-auc-to-optimize-vancomycin-dosing. (Accessed November 02, 2019).
    2. Heil E, Claeys K, Mynatt R et al. Making the change to area under the curve-based vancomycin dosing. American Journal of Health-Syst Pharm. 2018; 75: 1986-1995
    3. Moise-Broder P, Forest A, Birmingham M, et al. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory track infections. Clinical Pharmacokinet. 2004; 43:925-940
    4. Pai M, Neely M, Rodvoid K, et al. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Advanced Drug Delivery Reviews. 2014; 77: 50-57
    5. Neely M, Youn G, Jones B, et al. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrobial agents and Chemotherapy. 2014; 58:309-316
    6. Rybak M, Lomaestro B, Rotschafer J, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. American J. Health Syst. Pharm. 2009; 66:82-98
    7. Suzuki Y, Kawasaki K, Sato Y, et al. Is peak concentration needed in therapeutic drug monitoring of vancomycin? A pharmacokinetic-pharmacodynamic analysis in patients with methicillin-resistant Staphylococcus aureus pneumoniae. Chemotherapy. 2012; 58:308-312
    8. Elbarbry F. Vancomycin dosing and monitoring: critical evaluation of the current practice. Euro Journal of Drug Metab Pharmacokinet. 2018; 43:259-268
    9. Neely M, Kato L, Youn G et al. Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. American Society for Microbiology. 2018; 62: 204-217
    10. Chung J, Oh M, Cho E, et al. Optimal dose of vancomycin for treating methicillin-resistant Staphylococcus aureus pneumonia in critically ill patients. Anaesth. Intensive Care. 2011; 39: 1030-1037
    11. Hal v, Paterson D, Lodise T, et al. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. 2013; 57: 734-744
    12. Chevada R, Ghosh N, Sandaradura M, et al. Establishment of an AUC0-24 threshold for nephrotoxicity is a step towards individualized vancomycin dosing for methicillin-resistant Staphylococcus aureus bacteremia. Antimicob agents and Chemotherapy. 2017; 61:2535-16
    13. Jung Y, Song K, Cho J et al. Area under the concentration-time curve to minimum inhibitory concentration ratio as a predictor of vancomycin treatment outcome in methicillin-resistant Staphylococcus aureus bacteremia. Intl Journal of Antimicrobial agents. 2014; 43:179-183
    14. Hale M, Seabury R, Steele J et al. Are vancomycin trough concentrations of 15 to 20 mg/l associated with increased attainment of an AUC/MIC ≥ 400 in patients presumed with methicillin-resistant Staphylococcus aureus infection? Jour of Pharm Practice. 2017; 30: 329-335.

    Submit for CE

  • 17 Jan 2020 11:18 AM | Anonymous

    Author: Emily Shor, Pharm.D.

    Objectives:

    1. Identify the complications associated with early initiation of anticoagulation after an atrial fibrillation associated ischemic stroke.
    2. List differences between guideline recommendations regarding the initiation of anticoagulation after an ischemic stroke.
    3. Describe limitations of the available literature addressing the timing of anticoagulation initiation after an atrial fibrillation associated ischemic stroke.
    4. Describe patients who could be considered for early initiation of anticoagulation after an atrial fibrillation associated ischemic stroke.

    Approximately 13% to 26% of ischemic strokes occur in the setting of a cerebral embolism associated with non-valvular atrial fibrillation.1 Initiation of anticoagulation has been shown to be efficacious in secondary prevention of stroke, but the appropriate timing of anticoagulation initiation requires balancing efficacy and safety. After an atrial fibrillation associated ischemic stroke, the risk of recurrence of ischemic stroke within the subsequent 14 days increases by 0.5% to 1.3% per day when anticoagulation is not initiated.2 However, early initiation of anticoagulation is also associated with an increased risk of hemorrhagic transformation. Therefore, optimizing the timing of anticoagulation initiation proves to be a complex, yet common, challenge after an atrial fibrillation associated ischemic stroke.

    The risk of recurrent ischemic stroke and the risk of hemorrhagic transformation are two key considerations when determining the timing of anticoagulation initiation. To assess a patient’s risk of recurrent stroke, the CHA2DS2-VASc score can be utilized as a predictive model, particularly in patients with atrial fibrillation.3 Additionally, a larger ischemic lesion size at the time of the ischemic stroke is associated with an increased risk of recurrent stroke. Similarly, higher CHA2DS2-VASc score and large ischemic lesion size have been associated with an increased risk of hemorrhagic transformation, a common and serious complication of stroke that results in an ischemia-related brain hemorrhage.3 Risk factors for hemorrhagic transformation include massive cerebral infarction, area of infarction (grey matter), concurrent atrial fibrillation, higher National Institutes of Health Stroke Scale (NIHSS) score, hyperglycemia, low platelet count, poor collateral vessels, and use of thrombolytic therapy.4-5 Each of these factors should be assessed when determining when to initiate anticoagulation.

    While warfarin has served as the mainstay anticoagulant for patients with atrial fibrillation, direct oral anticoagulants (DOACs) have also proven to be efficacious for secondary prevention of stroke in patients with atrial fibrillation. However, the landmark trials that established the role of DOACs in stroke prevention in patients with atrial fibrillation largely excluded patients with recent ischemic strokes (Table 1). In the ARISTOTLE and ROCKET-AF trials, all patients with a documented history of stroke were enrolled at least a year after the index stroke event.6-7 Therefore, these landmark trials do not offer data regarding the optimal time to initiate DOACs after an ischemic stroke.

    Guideline Review

    Current guidelines addressing the management of patients with stroke offer varying strategies of initiating anticoagulation. The 2014 American Heart Association/American Stroke Association (AHA/ASA) Guidelines for Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack state that it is reasonable to initiate oral anticoagulation within 14 days after symptom onset (Class IIa; Level of Evidence B). In patients at high risk for hemorrhagic conversion (ex. large infarct, hemorrhagic transformation on initial imaging, uncontrolled hypertension, or hemorrhagic tendency), it is reasonable to initiate oral anticoagulation after 14 days (Class IIa; Level of Evidence B).10 In contrast, the 2016 European Society of Cardiology (ESC) Guidelines for the Management of Atrial Fibrillation recommend initiating an oral anticoagulant based on severity of stroke. Patients who experience a transient ischemic attack (TIA) should start anticoagulation one day after the event. Patients with a mild stroke (NIHSS < 8), moderate stroke (NIHSS 8-15), or severe stroke (NIHSS >16) should start anticoagulation three, six, or 12 days after the acute event, respectively. Although the 2016 ESC guidelines provide more specific recommendations, the recommendations are based on expert opinion.11 However, the 2016 ESC guidelines reflect more recent data that has been published since the 2014 AHA/ASA guidelines. The 2018 European Heart Rhythm Association (EHRA) Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation provide recommendations similar to the 2016 ESC guidelines. The EHRA recommends DOACs be continued or initiated one day after a TIA and exclusion of intracranial hemorrhage by imaging. If stroke size is not expected to increase risk of hemorrhagic transformation, oral anticoagulation should be initiated > 3 days, > 6-8 days, and > 12-14 days after a mild, moderate, or severe stroke, respectively.13

    Literature Review

    Randomized controlled trials assessing the optimal time frame to initiate anticoagulation in patients with atrial fibrillation associated ischemic stroke are lacking. The RAF study evaluated the risk of recurrent ischemic events and severe bleeding in patients with acute stroke and atrial fibrillation and sought to identify the risk factors for these events. This international, prospective, multicenter study enrolled 766 patients, including 284 (37%) receiving vitamin K antagonists (VKAs) alone, 276 (36%) receiving VKA after low molecular weight heparin (LMWH), 113 (15%) receiving LMWH alone, and 93 (12%) receiving a DOAC. Mean NIHSS score on admission was 11.9 among patients who received LMWH alone, 6.9 among patients who transitioned from LMWH to oral anticoagulation, and 8.3 among patients who received oral anticoagulation alone. Mean time to anticoagulation initiation after ischemic stroke onset was 8.5 days, 6.5 days, and 12.1 days in the DOAC, LMWH, and VKA groups, respectively. Overall, 123 patients experienced 128 outcome events, including ischemic stroke/TIA/systemic embolism (7.6%), symptomatic intracranial bleeding (3.6%), and major extracerebral bleeding (1.4%). An adjusted analysis determined that anticoagulation initiation between four to 14 days from stroke onset was associated with a significant decrease in all outcome events (HR: 0.53; 95% CI: 0.3-0.93; p=0.025) and ischemic outcome events (HR: 0.43; 95% CI: 0.19-0.97; p=0.043) and a nonsignificant decrease in symptomatic cerebral bleeding (HR: 0.39; 95% CI 0.12-1.19; p=0.09). Predictive factors for primary outcomes included increased CHA2DS2-VASc score, large lesion size, and type of anticoagulant used after stroke. Use of LMWH after stroke increased symptomatic intracranial bleeding incidence. Ultimately, the RAF study concluded that the safest time to initiate anticoagulation as secondary prevention is four to 14 days.3

    A nonrandomized cohort analysis of the Virtual International Stroke Trials Archive (VISTA) described contrasting results compared to the RAF study. The VISTA analysis enrolled 1644 patients, including patients receiving VKA alone (31%), VKA and antiplatelets (48%), or antiplatelets alone (10%). Median time to anticoagulation initiation was two days, and median NIHSS score among patients receiving anticoagulants was 14. Among patients receiving antithrombotics, 10% experienced an ischemic stroke, and 3% experienced a symptomatic intracerebral hemorrhage at 90 days. The VISTA analysis concluded that initiation of anticoagulation within two to three days post-stroke decreased risk of recurrent stroke without a significant increase in bleeding events. While the differences in findings as compared to the RAF study can be attributed to differences in populations (ex. baseline NIHSS score), concomitant medications, and study design, the VISTA analysis suggests that there may be a population that may benefit from earlier initiation of anticoagulation as compared to the four to 14 day recommendation derived from the RAF study.13

    DOACs are being utilized more frequently as they are associated with a lower risk of bleeding events as compared to VKAs in the general population. Overall, in the RAF study, 93 patients received a DOAC, and six of these patients experienced an outcome event at 90 days. The RAF-NOACs study subsequently evaluated the rates of recurrent ischemic embolic or severe bleeding events and their timing in patients with atrial fibrillation who develop an ischemic stroke and are initiated on a DOAC. This international, prospective, observational, multicenter study enrolled 395 patients receiving dabigatran, 376 patients receiving rivaroxaban, and 390 patients receiving apixaban. Median time to anticoagulant initiation after ischemic stroke was eight days for dabigatran and rivaroxaban groups and seven days for the apixaban group. Overall mean NIHSS score on admission was 7.7. At 90 days, ischemic stroke occurred in 2% of all patients (dabigatran group: 1.3%; apixaban group: 2.6%; rivaroxaban: 1.9%). The combined endpoint of ischemic stroke, symptomatic hemorrhagic transformation, or serious extracranial bleeding occurred in 5.2% of all patients (dabigatran group: 2.9%; apixaban group: 7.4%; rivaroxaban: 5.5%). These event rates were significantly lower than those reported in the RAF study, indicating this may be a lower risk population or suggesting an overall decreased rate of events in patients receiving DOACs as compared to warfarin. Initiation of anticoagulation within three to 14 days of stroke event was associated with a composite event rate of 2.1% as compared to 12.4% among patients who initiated anticoagulation within two days and 9.1% among patients who initiated anticoagulation after 14 days. However, timing of DOAC initiation was not found to be directly correlated to event rates, so the optimal timing of anticoagulation initiation cannot be inferred from this data. Similar to the RAF study, bridging with therapeutic LMWH preceding an oral anticoagulant was associated with an increased risk of primary composite events (OR: 4.13; 95% CI: 1.73-8.96; p=0.0003), ischemic outcome events (OR: 3.73; 95% CI: 0.95-10.63; p=0.01); and hemorrhagic outcome events (OR: 4.75; 95% CI: 1.60-12.32; p=0.0009). However, confounding variables, such as baseline NIHSS score, thrombotic risk, and bleed risk, may contribute to these patients’ increased risk of outcome events.14

    The CROMIS-2 study was a post-hoc analysis of a prospective, multicenter, observational cohort study that evaluated oral anticoagulant timing in relation to 90-day clinical outcomes (composite of ischemic stroke, TIA, intracranial hemorrhage, or death due to any cause). Seven of 358 patients (2%) who received anticoagulation early (within four days of ischemic event) experienced an event as compared to 48 of 997 patients (5%) who initiated anticoagulation five days or later after an ischemic event. However, patients who were initiated on anticoagulation within four days of an ischemic event had a lower NIHSS score, smaller infarcts, and less frequent incidence of hemorrhagic transformation on index imaging. The CROMIS-2 study concluded that starting anticoagulation within four days, particularly in patients with milder strokes, no thrombolysis, and better pre-stroke functioning as defined by modified Rankin Scale, could be considered for initiation of anticoagulation within four days of ischemic stroke.15

    Overall, while these observational studies provide guidance regarding anticoagulation initiation after an atrial fibrillation associated ischemic stroke, there are numerous limitations regarding their study designs and the generalizability of their results. For example, the observational study designs introduce selection bias from the provider, introducing confounding that cannot be controlled. Additionally, the dosing of anticoagulation was not included in these studies, which may contribute to differences in outcomes. While baseline thrombotic risk and stroke severity were reported, baseline bleeding risk was not assessed, which may be a valuable tool in determining which patients are at an increased risk of hemorrhagic transformation.3,13-15

    Conclusions

    Recent European guidelines recommend determining the appropriate timing of anticoagulation initiation based on stroke severity as compared to the 2014 AHA/ASA guidelines. However, guidelines generally recommend initiation of anticoagulation within 14 days of stroke symptom onset and delaying initiation of anticoagulation in patients with risk factors for hemorrhagic transformation. Patient specific factors, including size of lesion, NIHSS score upon presentation, CHA2DS2-VASc score, and risk of bleeding should be considered when deciding when to initiate anticoagulation within the three to 14 day window. Earlier initiation within this window (closer to four days after ischemic event) can be considered in patients with lower NIHSS score (<8), no thrombolysis, better pre-stroke functioning, smaller lesion size, and low bleeding/hemorrhagic conversion risk.

    References

    1. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation. 2018;137(12):e67-e492.
    2. Grau AJ, Weimar C, Buggle F, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke. 2001;32(11):2559-66.
    3. Paciaroni M, Agnelli G, Falocci N, et al. Early recurrence and cerebral bleeding in patients with acute ischemic stroke and atrial fibrillation: effect of anticoagulation and its timing: the RAF study. Stroke. 2015;46(8):2175-82.
    4. Zhang J, Yang Y, Sun H, Xing Y. Hemorrhagic transformation after cerebral infarction: current concepts and challenges. Ann Transl Med. 2014;2(8):81.
    5. Tu HT, Campbell BC, Christensen S, et al. Worse stroke outcome in atrial fibrillation is explained by more severe hypoperfusion, infarct growth, and hemorrhagic transformation. Int J Stroke. 2015;10(4):534-40.
    6. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91.
    7. Granger CB, Alexander JH, Mcmurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-92.
    8. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51.
    9. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-104.
    10. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160-236.
    11. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38):2893-2962.
    12. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39(16):1330-1393.
    13. Abdul-Rahim AH, Fulton RL, Frank B, et al. Association of improved outcome in acute ischaemic stroke patients with atrial fibrillation who receive early antithrombotic therapy: analysis from VISTA. Eur J Neurol. 2015;22(7):1048-55.
    14. Paciaroni M, Agnelli G, Falocci N, et al. Early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with non-vitamin-K oral anticoagulants (RAF-NOACs) study. J Am Heart Assoc. 2017;6(12):1-13.
    15. Wilson D, Ambler G, Banerjee G, et al. Early versus late anticoagulation for ischaemic stroke associated with atrial fibrillation: multicentre cohort study. J Neurol Neurosurg Psychiatry. 2019;90(3):320-325.

    Submit for CE

  • 17 Jan 2020 11:15 AM | Anonymous

    Author: Nathan Hanson, PharmD, MS, BCPS

    Legislative Day is April 1st - will you be joining us? No, this isn’t a practical joke…advocacy is our job! Why? Because advocacy is leadership in action.

    The playoffs are here, and what a year it’s been already! And like most years, this year we have been reminded how important the rules are. We see games decided and seasons completely changed because of one rule and one referee’s interpretation of that rule. Players can only do what they do best when they have the right rules, and when there is a clear understanding of those rules.

    This brings us to pharmacy. Like the players, we are only able to use our skills and play the game within the rules that we have been given. Our patients need us to advocate for the best rules that allow pharmacists to provide the care that they need. Our patients need us to understand the rules so that we can safely and creatively serve their needs. Luckily, by joining MSHP you have already taken the first and most important step in the advocacy process. Over the next few MSHP newsletters we will we review the simple next steps that you can take to advocate for your patients.

    We need to make up our minds that advocacy is indeed our job. Remember, advocacy just means that we work hard to

    Understand the current rules so we follow them correctly

    Improve the rules, using the systems that are in place.

    When described this way, it makes it clear that advocacy is part of every pharmacy leader’s job.

    Why is advocacy part of a pharmacy leader’s job? Pharmacists and technicians are committed to creative problem solving, quality assurance, and quality improvement. But we can only solve problems within the rules of the game, and we can’t assure quality unless we know what quality is, and we can make the biggest improvements to quality when we adjust the rules to allow innovative approaches. Every year our pharmacy schools train outstanding students, and every year our residencies provide even more training. But where to deploy all of that talent and passion? The potential can only be fully realized when we advocate for our patients.

    I’ll leave you with a little light reading. First, the ASHP statement on advocacy as a professional obligation:

    “ASHP believes that all pharmacists have a professional obligation to advocate on behalf of patients and the profession. Pharmacists should stay informed of issues that affect medication-related outcomes and advocate on behalf of patients, the profession, and the public. These issues may include legal, regulatory, financial, and other health policy issues, and this obligation extends beyond the individual practice site to their broader communities.”1

    Next, a letter from Scott Knoer and Erin Fox that lays out some practical steps to take in our advocacy journey2 and an article3 showing the value of participating in a Legislative Day. Of course you can’t do everything, but it’s a new year for a fresh start! By attending Legislative Day or choosing to do one of these things in 2020 you can demonstrate Leadership in Action by advocating for our patients and our profession.

    Advocacy is our job – let’s decide to do it well!

    1. Jeff Little, Melissa Ortega, Michael Powell, Mark Hamm, ASHP Statement on Advocacy as a Professional Obligation, American Journal of Health-System Pharmacy, Volume 76, Issue 4, 15 February 2019, Pages 251–253, https://doi.org/10.1093/ajhp/zxy040
    2. Scott Knoer, Erin R Fox, Advocacy as a professional obligation: Practical application, American Journal of Health-System Pharmacy, , zxz328, https://doi.org/10.1093/ajhp/zxz328
    3. Kate Traynor, Pharmacists make advocacy happen on ASHP Legislative Day, American Journal of Health-System Pharmacy, Volume 77, Issue 2, 15 January 2020, Pages 69–70, https://doi.org/10.1093/ajhp/zxz296


  • 15 Jan 2020 1:08 PM | MSHP Office (Administrator)

    Author: Becca Nolen, Pharm.D., BCPS, BCIDP, AAHIVP Member, MSHP Research and Education Foundation

    The local ASHP Clinical Skills Competition winners from both the St. Louis College of Pharmacy and the University of Missouri-Kansas City were recognized during the MSHP reception at Midyear. Congratulations to William Miller & Blake Robbins from STLCOP and Amelia Gooch & Garrett Matthews from UMKC! Thank you for representing Missouri!

    MSHP R&E Foundation is currently accepting submissions and nominees for two awards. The deadline for all submissions and nominations will be Friday, January 31st.

    Garrison Award

    The Garrison award was established in 1985, named after Thomas Garrison for his long standing support of MSHP (past-president 1974-1976), ASHP (past-president 1984) and numerous professional and academic contributions to Pharmacy. The Garrison Award is presented each year to a deserving candidate who has been nominated in recognition of sustained contributions in multiple areas:

    • Outstanding accomplishment in practice in health-system pharmacy;
    • Outstanding poster or spoken presentation at a state or national meeting;
    • Publication in a nationally recognized pharmacy or medical journal;
    • Demonstrated activity with pharmacy students from St. Louis or the UMKC Schools of Pharmacy;
    • Development of an innovative service in a health-system pharmacy in either education, administration, clinical service, or distribution;
    • Contributions to the profession through service to ASHP, MSHP and/or local affiliates.

    Each letter of nomination must include:

    • Name, work address, and telephone number of nominee;
    • Name, work address, and telephone number of nominator;
    • Sufficient explanation and documentation of the nominee’s accomplishment(s) to allow a proper decision by the selection committee;
    • and Curriculum Vitae of the Nominee.
    • To be considered for the Garrison Award, the nominee must be a current active member of the Missouri Society of Health-System Pharmacists. The winner will be selected by the Board of Directors of the MSHP Research and Education Foundation. Email your nomination to mshp@qabs.com with Garrison Award Submission in the subject line.

    Tonnies Preceptor Award

    MSHP R&E Foundation is pleased to honor a health system pharmacist for outstanding service to the profession as a preceptor to pharmacy students and/or residents. Below are the Criteria and Procedures to nominate a preceptor for the award.

    The Tonnies Preceptor award was established in 2020, named after Fred Tonnies, Jr. for his long standing support of MSHP (past-president 1976-1978), Mid-Missouri Society of Hospital Pharmacists (MMSHP) (past-president 1988) and numerous professional and academic contributions to Pharmacy. He was one of the founding members of MSHP and MMSHP, and has over 35 years of precepting experience. The Tonnies Preceptor Award is presented each year to a deserving candidate who has been nominated in recognition of sustained contributions in multiple areas:

    • Outstanding accomplishment in precepting learners in health-system pharmacy;
    • Sustained contribution to mentoring students/residents in the research process;
    • Demonstrated activity with pharmacy students from St. Louis or the UMKC Schools of Pharmacy;
    • Contributions to the profession through service to ASHP, MSHP and/or local affiliates.

    Eligibility:

    1. Must be a member of MSHP;
    2. Must have sustained practice as a clinical preceptor over 10 years;
    3. Must have not received the award;
    4. The winner will be selected by the Board of Directors of the MSHP Research and Education Foundation. Email your nomination to mshp@qabs.com with Tonnies Award Submission in the subject line.

    Criteria:

    The award will be presented to a health system pharmacist that consistently exemplifies the core values (Professionalism, Desire to educate and share knowledge with students, Willingness to mentor, Willingness to commit the time necessary for precepting, Respect for others, Willingness to work with a diverse student population) and the following characteristics:

    1. Partner in education: Is actively involved in instructing and educating in pharmacy practice
    2. Role model: Demonstrates willingness to mentor and serve as an example
    3. Experience: Has depth of experience and knowledge in area of expertise
    4. Coaching: Provides timely and meaningful feedback to the learner
    5. Enthusiasm: Demonstrates passion towards the profession and advancement of practice
    6. Professionalism: Conducts himself/herself with highest level of dignity and professionalism
    7. Teamwork: Facilitates team work and approach to patient care
    8. Opportunity: Creates innovative learning experiences and opportunities to for growth
    9. Research: Makes regular contributions to the profession through papers or presentations
    10. Investment: Demonstrates enthusiasm in developing future practitioners and leaders

    Each letter of nomination must include:

    • Name, work address, and telephone number of nominee;
    • Name, work address, and telephone number of nominator;
    • Sufficient explanation and documentation of the nominee’s accomplishment(s) to allow a proper decision by the selection committee;
    • and Curriculum Vitae of the Nominee.
    • To be considered for the Tonnies Preceptor Award, the nominee must be a current active member of the Missouri Society of Health-System Pharmacists. The winner will be selected by the Board of Directors of the MSHP Research and Education Foundation. Email your nomination to mshp@qabs.com with Tonnies Preceptor Award Submission in the subject line.


  • 14 Nov 2019 1:23 PM | MSHP Office (Administrator)

    Author: Cara Carter, PharmD

    As we delve deeper in to flu season, we are reminded of one of the greatest public health advances but also one of the biggest controversies of our time: immunizations. In the aftermath of Andrew Wakefield’s falsified article linking the MMR vaccine to autism as well as the support of the anti-vax movement from celebrities like Jenny McCarthy and Jim Carey, we are seeing a resurgence of diseases once deemed to be eradicated.1 As the winter season sets in and people spend more time indoors, they will be in close quarters with many people whose immunization and infection status may be unknown to them. It is important that we, as healthcare providers, are diligent in protecting our patients and doing our part to help prevent outbreaks. We can be actively involved in this effort by being prepared to mitigate vaccine hesitancy.

    Vaccine hesitancy is a delay in acceptance or refusal of vaccines despite availability of vaccination services.2 Though reasons for vaccine hesitancy are many, they fit in to 3 categories: confidence, complacency, and convenience. Confidence is the trust in the effectiveness and safety of vaccines, the system that delivers vaccines, competence of healthcare professionals, and the motives of those who establish policies on necessary vaccines.3 Being honest about vaccine side effects and reassuring parents of their safety can have an impact on confidence. This builds trust in the provider which is also shown to have a positive effect on vaccine compliance.4 In order to be successful in this endeavor, we, as health care providers, must be intentional in remaining current on vaccine information and providing reliable sources of information to patients and families who may be struggling with confidence.

    Complacency is the perception that risks of vaccine-preventable diseases are low and vaccines are not a necessary preventative action.3 Honest conversations about acute and chronic complications of vaccine preventable diseases and personal anecdotal evidence are appropriate measures for combatting complacency. Cases of measles have been reported in the state of Missouri just this year with outbreaks also being reported in El Paso, TX; Rockland County, NY; New York City, NY; Los Angeles County, CA; and multiple counties in the state of Washington.5 Anecdotal evidence that includes what the provider would do or has personally done for his or her children and prior experiences with vaccine safety have been shown to be effective according to a survey of primary care physicians in the United States.4

    Convenience is the extent to which vaccines are available, affordable, accessible, understood (language and health literacy), and appealing.3 Offering vaccine services at every clinic visit, before hospital discharge, and during prescription pick-up as well as informing patients of community resources such as immunization clinics and free or reduced cost immunization programs are a few ways that we can help overcome the issue of convenience. If additional issues related to convenience arise, such as lack of transportation, consider social work consultation to aid in resolution of the issues.

    From physicians to nurses, pharmacists to social workers, we all play a vital role in reducing vaccine hesitancy. Vaccine hesitancy is not an easy issue to combat, and may take more than one visit and assistance from more than one provider to put parents and patients at ease. We should not find this as a point of frustration or discouragement but, rather inspiration to keep growing and learning as practitioners. Did the patient have a question you could not answer? Was an issue brought up that you were unsure how to address? Use those as starting points of a literature search or questions to pose to colleagues for their insight. It is important for us to remember that the goal is to put parents and patients at ease while assuring them that they, too, are a part of the team. Our collective goal as a healthcare team is to do what is in the best interest of the patient because, as American author John C. Maxwell has taught us, “Teamwork makes the dream work.”

    References
    1. Centers for Disease Control and Prevention. Measles History. Available at: https://www.cdc.gov/measles/about/history.html. Accessed July 26, 2019.
    2. MacDonald NE, the SAGE Working Group on Vaccine Hesitancy. Vaccine hesitancy: Definition, scope and determinants. Vaccine 2015;33(34):4161-4.
    3. Strategic Advisory Group of Experts on Immunization, World Health Organization. Report of the SAGE Working Group on Vaccine Hesitancy. Available at: https://www.who.int/immunization/sage/meetings/2014/october/1_Report_WORKING_GROUP_vaccine_hesitancy_final.pdf. Accessed July 26, 2019
    4. Shen SC, Dubey V. Addressing vaccine hesitancy: Clinical guidance for primary care physicians working with parents. Le Medécin de famille canadien 2019;65:175-81.
    5. Centers for Disease Control and Prevention. Measles Cases and Outbreaks. Available at: https://www.cdc.gov/measles/cases-outbreaks.html. Accessed July 26, 2019.


  • 14 Nov 2019 1:08 PM | MSHP Office (Administrator)

    Authors: Colton Frazer, PharmD Candidate 2022 and Paul Juang, Pharm.D, BCPS, BCCCP, FASHP, FCCM

    2019 CDC Vaccine Schedule Changes

    Vaccines are an imperative part of the success of the modern health system. However, vaccines are only effective when utilized correctly. Due to the intricacies of the vaccination schedule, and the continually evolving contraindications, reviewing the Center for Disease Control’s vaccination schedule can be a valuable method of staying up to date from year to year. In this review of the CDC’s 2019 vaccination schedule, a few recent changes will be highlighted, Shingrix and Pneumococcal guidelines will be refreshed, and the new hexavalent vaccine, VaxelisTM, will be discussed. 

    Notable Changes as of February 2019:

    Influenza Vaccine:

    As of 2019 the Live Attenuated Influenza Vaccine (LAIV) has been listed separately from the Inactive Influenza Vaccine (IIV) and Recombinant Influenza Vaccine (RIV). Moreover, LAIV is suitable for ages 2 years through 49 years old. Absolute contraindications in adult and children patients for LAIV include immunocompromising conditions (including HIV infection), anatomical or functional asplenia, pregnancy, close contact with severely immunocompromised persons, received influenza antiviral medications in the previous 48 hours, cerebrospinal fluid leak, cochlear implant, asthma (5 years or older). Other problematic underlying medical conditions (e.g., chronic pulmonary, cardiovascular [except isolated hypertension], renal, hepatic, neurologic, hematologic, or metabolic disorders [including diabetes mellitus])


    If any of the above LAIV contraindications apply to the patient, then the CDC recommends the IIV or RIV as a safe alternative.

    Hepatitis A Vaccine:

    A new indication for HepA vaccine has been added, homelessness. This is because being homeless has been linked with a two to three times higher chance of contracting hepatitis A, as well as displaying more severe outcomes from the disease when compared to non-homeless. For this new indication there are 2 options: get a 2-dose series of single-antigen hepatitis A vaccine or a 3-dose series of hepatitis A and hepatitis B vaccine. Moreover, there is a new pediatric international travel recommendation for vaccination of patients age 6 - 11 months and for all travelers greater than 12 months of age.

    Hepatitis B Vaccine:

    The hepatitis B have been updated to a 2-dose Heplisav-B® given at least 4 weeks apart. As needed, it can be switched to 3-dose series of Engerix-B vaccine. The seroprotection of the two vaccine sets shows that the newer Heplisav-B® is the preferred method when possible. (65%-81% for Engerix-B vs. 90%-95% for Heplisav-B®)


    Common Vaccination Review

    Shingrix:

    The Shingrix vaccine is recommended by the CDC for immunocompetent people older than 50 years, and is to be given in a two shot series separated by 2 - 6 months. This is regardless of previous herpes zoster episodes, taking low-dose immunosuppressives/are anticipating immunosuppression, or have recovered from an immunocompromising disease.

    For patients who have had previous episodes of herpes zoster, there is no set time to wait to receive the Shingrix vaccine. However, Shingrix is not to be administered to patients with active herpes zoster infections. If the patient has recently received Zostavax®, it is recommended to wait at least 8 weeks before administering Shingrix.

    Contraindications include allergies to any component of Shingrix, seronegative to varicella, acute episode of herpes zoster, or women who are pregnant or breastfeeding

     

    PCV13 and PPSV23 in Children and Adults

    All infants should receive the PCV13 immunization at 2, 4, and 6 months old. Then, a booster should be administered at age 12 - 15 months. Furthermore, all adults 65 years and older are recommended to receive the pneumococcal vaccine. If the adult has never received a dose of PCV13 before, administer this first. One year later, the PPSV23 should be administered. If the adult has received their dose of PPSV23 already, then administer the PCV13 at least one year after. 


    Vaxelis

    In December 2018, the FDA approved VaxelisTM to vaccinate children between 6 weeks old and 4 years old. VaxelisTM is indicated to prevent diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type b, and poliomyelitis. VaxelisTM is administered as a 3-shot series starting at the age of 6 weeks old, and ending before the child is 5 years old. This vaccine is a combo product, combining antigens for diphtheria, tetanus, pertussis, and poliomyelitis from drug company Sanofi, and antigens for H. influenzae type b and hepatitis B from drug company Merck. After receiving the 3-dose series of VaxelisTM, the child will still need to receive one additional pertussis shot to complete their immunizations to the agent. By using this combo-vaccine a child can receive their Hepatitis B series in 4 or 5 shots, compared to the normal 6 to 8 using conventional Hep. B vaccination series. Below is a chart illustrating the advantage of using the VaxelisTM vaccination series compared to alternative options.

    VaxelisTM is expected to be available for use by 2020.


    References:

    All information and pictures sourced from www.cdc.gov/vaccines.

    For any further information, or to check the most recent vaccination guidelines, please visit


  • 14 Nov 2019 12:48 PM | MSHP Office (Administrator)

    Authors: Mary Thorne, PharmD, PGY1 Pharmacy Resident and Kathryn Lincoln PharmD, BCPS, BCIDP, Clinical Pharmacist – Infectious Diseases, Olathe Medical Center

    Learning Objectives

    1. Provide background information on community acquired pneumonia (CAP)
    2. Explain the updated guidelines and the rationale behind the recommendations
    3. Compare the 2007 guideline to current guideline recommendations
    4. Summarize current recommendations for management of CAP

    Introduction

    The American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) developed updated guidelines for community-acquired pneumonia (CAP) and were released in October this year. The 2007 CAP guidelines were preceded by the 2005 ATS Guidelines for the Management of Adults with Hospital-acquired (HAP), Ventilator-associated (VAP), and Healthcare-associated Pneumonia (HCAP). In 2016, IDSA and ATS released Management of Adults with Hospital-acquired and Ventilator-associated Pneumonia, leaving out HCAP. Since their release, there has been controversy and much debate about how to manage patients that may have community-acquired pneumonia, but are more at risk than the general population for multi-drug resistant organisms (MDRO). More literature has become available for the management of CAP since the 2007 guidelines, including patients at risk for MDRO.

    Community-acquired pneumonia is defined as pneumonia that is acquired outside of the hospital setting. Common pathogens for CAP include Haemophilus influenza, Legionella species, Chlamydophila pneumoniae, Moraxella catarrhalis, Streptococcus pneumoniae, Staphylococcus aureus, and Mycoplasma pneumoniae.

    Recommendation #1

    In adults with CAP, recommend against obtaining sputum gram stain and culture routinely in adults with CAP managed in the outpatient setting (strong recommendation, very low quality of evidence).

    Pre-treatment gram stain and culture of respiratory secretions should be obtained for adult patients with CAP in the hospital setting who are classified as severe CAP. Severe CAP being patients who were empirically treated for MRSA or P. aeruginosa, previously infected with MRSA or P. aeruginosa, hospitalized and received parenteral antibiotics in the past 90 days.

    Studies did not show improved patient outcomes when evaluating sputum gram stain and culture either in combination or alone. Research is still needed for guidance on rapid, cost effective diagnostics to help identify organisms causing CAP and improve targeted therapy when there are risk factors for MRSA and P. aeruginosa.

    Recommendation #3

    In adults with CAP, recommend against routinely testing urine antigens in adults with CAP, except patients with severe CAP or in cases where indicated by epidemiological factors such as association with a Legionella outbreak or recent travel (conditional recommendation, low quality of evidence).

    Randomized trials have not shown benefit for urinary antigen testing for S. pneumoniae and Legionella. There is concern that narrowing therapy in response to positive urinary antigen tests could lead to increased risk of clinical relapse.

    Recommendation #4

    In adults with CAP, recommend during influenza season, test for influenza with a rapid influenza molecular assay (strong recommendation, moderate quality of evidence).

    During periods of high influenza activity, it is beneficial to utilize a rapid influenza test. Testing provides both therapeutic and infection control benefits.

    Recommendation #5

    In adults with CAP, recommend empiric antibiotic therapy initiated in adults with clinically suspected and radiographically confirmed CAP regardless of initial serum procalcitonin (strong recommendation, moderate quality of evidence).

    Procalcitonin is used to guide de-escalation, discontinuation and duration of antibiotics in patients with lower respiratory infections. The sensitivity of procalcitonin for detecting bacterial infection ranges from 38% to 91%. This test alone cannot be used to justify withholding antibiotics from patients with CAP.

    There is not an established procalcitonin threshold for determining viral versus bacterial pathogens in hospitalized patients with CAP. However, there is a strong correlation with a higher procalcitonin and the probability of a bacterial infection.

    Recommendation #6

    Clinicians should use a prediction rule for prognosis, preferentially the Pneumonia Severity Index (PSI) (strong recommendation, moderate quality of evidence).

    PSI should be used as a supplement to clinical judgment. There is evidence confirming the safety and effectiveness of using PSI in addition to clinical judgment as a prognostic tool. PSI is a prognostic model in immunocompetent patients with pneumonia using demographic and clinical variables from the time of diagnosis to predict 30-day mortality.


    Recommendation #8

    In the outpatient setting, antibiotics are recommended for empiric treatment of CAP in adults.  For healthy outpatient adults without comorbidities or risk factors for antibiotic resistant, the following is recommended: 

    • Amoxicillin 1g PO TID or
    • Doxycycline 100mg PO BID or
    • Macrolide: only in areas with pneumococcal resistance to macrolides < 25%
      • Azithromycin 500mg on first day then 250mg daily

    Outpatient adults with comorbidities such as chronic heart, lung, liver, or renal disease, diabetes mellitus, alcoholism, malignancy, or asplenia, the treatment options include monotherapy with a respiratory fluoroquinolone or combination therapy with a beta lactam plus a macrolide or a beta lactam plus doxycycline. There is limited evidence regarding the superiority or equivalency of antibiotic regimens for the treatment of CAP. 


    Recommendation #9

    For inpatient adults with non-severe CAP without risk factors for MRSA or P. aeruginosa, treatment options include monotherapy with a respiratory fluoroquinolone or combination therapy of a beta lactam plus a macrolide or combination of beta lactam plus doxycycline.

    For inpatient adults with severe CAP without risk factors for MRSA or P. aeruginosa, treatment recommendation includes a beta lactam plus a macrolide or a beta lactam plus a respiratory fluoroquinolone.

    In the absence of RCTs evaluating therapeutic alternatives in severe CAP, the evidence is from observational studies. The use of fluoroquinolones as monotherapy in severe CAP has not been well studied. There is also limited studies for the combination of a β-lactam and doxycycline in severe CAP patients. These treatment strategies are not recommended as empiric therapy for severe CAP.


    Recommendation #10

    In the inpatient setting, suggest not routinely adding anaerobic coverage for suspected aspiration pneumonia unless lung abscess or empyema is suspected (conditional recommendation very low quality of evidence).

    Older studies showed high rates of isolated anaerobic organisms in patients with aspiration pneumonia. However, more recent studies show that anaerobes are uncommon in hospitalized patients who are suspected to have aspiration pneumonia.

    Aspiration is a common occurrence and it is difficult to provide a true rate of aspiration pneumonia. Aspiration pneumonitis is when patients aspirate their gastric contents. More recent studies have suggested that anaerobes do not impact the causation and disease state of acute aspiration pneumonia.

    Recommendation #11

    Recommend abandoning use of the prior categorization of healthcare-associated pneumonia (HCAP) to guide selection of extended antibiotic coverage in adults with CAP (strong recommendation, moderate quality of evidence).

    If there are locally validated risk factors for the presence of MRSA or P. aeruginosa, clinicians should empirically cover for MRSA or P. aeruginosa in adults with CAP. HCAP was introduced due to studies showing a higher prevalence drug resistant pathogens. More recent studies have shown there is not a predicted higher prevalence of drug resistant pathogens when using the factors that define HCAP. The recommendation to abandon the category of HCAP is based on high-quality studies of patient outcomes.

    In most settings, studies have shown there is not a predicted higher prevalence of antibiotic-resistant pathogens, when using the factors that define HCAP. Patient outcomes have not improved despite a large increase in the use of broad spectrum antibiotics. Prior isolation of MRSA or P. aeruginosa is a strong risk factor when assessing a patient’s risk of having a respiratory infection with either MRSA or P. aeruginosa.  

    Recommendation #12

    Recommend not routinely using corticosteroids in adults with non-severe or severe CAP (strong recommendation, high quality of evidence).

    In patients with non-severe CAP, there is no evidence for mortality or organ failure benefit with the use of corticosteroids. There is limited data for the use of corticosteroids in patients with severe CAP. The risks of corticosteroids are hyperglycemia primarily, possibly increased rates of re-hospitalization and the potential for more complications.


    Recommendation #13

    Recommend anti-influenza treatment be prescribed for adults with CAP who test positive for influenza in the inpatient and outpatient setting, independent of duration of illness before diagnosis (strong recommendation, moderate quality of evidence).

    Clinical trials have not evaluated the effect of anti-influenza treatment in adult patients with influenza pneumonia. In the outpatient setting, it is unclear whether or not there is benefit to using anti-influenza treatment for patients who have tested positive for the influenza virus. 

    Recommendation #14

    Recommend that standard antibacterial treatment be initially prescribed for adults with clinical and radiographic evidence of CAP who test positive for influenza in the inpatient and outpatient settings (strong recommendation, low quality of evidence).

    A bacterial pneumonia infection can overlap with an active influenza viral infection. In patients recovering from a primary influenza infection, bacterial pneumonia may present later on, as worsening of symptoms. Patients are at risk for a concurrent infection of S. aureus bacterial pneumonia associated with influenza. The recommendation to treat patients with an antibacterial agent is based on the current evidence suggesting that bacterial co-infections with influenza can become complicated.

    Recommendation #15

    The duration of antibiotic therapy should be guided by a validated measure of clinical stability and antibiotic therapy should be continued until the patient achieves stability and for no less than a total of five days (strong recommendation, moderate quality of evidence).

    There are a few randomized trials addressing the appropriate duration for the treatment of patients with CAP. Despite limited data supporting a five-day treatment duration, it is recommended to treat patients for a minimum of five days even if a patient is clinically stable before five days. Clinical stability is the resolution of vital sign abnormalities such as, heart rate, respiratory rate, blood pressure, oxygen saturation, and temperature.

    Recommendation #16

    In adults with CAP whose symptoms have resolved within 5 to 7 days, we suggest not routinely obtaining follow-up chest imaging (conditional recommendation, low quality of evidence). 

    Data is limited when evaluating the utility of reimaging patients with pneumonia. More research may help to clarify any potential benefit to patients who need further radiology imaging after initial treatment.


    Summary

    Recommend abandoning use of HCAP to guide selection of extended antibiotic coverage in adults with CAP. Emphasis on local epidemiology and validated risk factors to determine need for MRSA or P. aeruginosa coverage. For standard empiric treatment of severe CAP, stronger evidence is in favor of β-lactam plus macrolide combination compared to β-lactam plus fluoroquinolone. 


    References

    1. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67.
    2. Self WH, Balk RA, Grijalva CG, Williams DJ, Zhu Y, Anderson EJ, et al. Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia. Clin Infect Dis 2017;65:183–190.
    3. El-Solh AA, Pietrantoni C, Bhat A, Aquilina AT, Okada M, Grover V, et al. Microbiology of severe aspiration pneumonia in institutionalized elderly. Am J Respir Crit Care Med 2003;167:1650–1654
    4. Marik PE, Careau P. The role of anaerobes in patients with ventilator associated pneumonia and aspiration pneumonia: a prospective study. Chest 1999;115:178–183 Intensive Care Med 1993;19:279–284.
    5. Kollef MH, Shorr A, Tabak YP, Gupta V, Liu LZ, Johannes RS. Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database of culture-positive pneumonia. Chest 2005;128:3854–3862
    6. Attridge RT, Frei CR, Pugh MJ, Lawson KA, Ryan L, Anzueto A, et al. Health care-associated pneumonia in the intensive care unit: guideline-concordant antibiotics and outcomes. J Crit Care 2016; 36:265–271.
    7. Attridge RT, Frei CR, Restrepo MI, Lawson KA, Ryan L, Pugh MJ, et al. Guideline-concordant therapy and outcomes in healthcare associated pneumonia. Eur Respir J 2011;38:878–887.


  • 14 Nov 2019 12:38 PM | MSHP Office (Administrator)

    Authors: Harrison Yoon, PharmD Candidate 2020 and Julianne Yeary, Pharm.D.

    Introduction

    Vancomycin-resistant enterococcus (VRE) is an emerging drug-resistant organism responsible for increasing numbers of hospital-acquired infections. It readily colonizes the intestines without any symptoms, which can serve as an infection reservoir and spread quickly among hospitalized patients.1 In 2013, the Centers for Disease Control and Prevention (CDC) estimated 20,000 cases of nosocomial VRE infections in the United States with 1,300 cases resulting in death.2

    VRE bacteremia is associated with significant mortality rates and prolonged hospital stays.3,4 Limited treatment options are available for VRE bacteremia. IDSA Guidelines recommend both daptomycin and linezolid as first-line agents for the treatment of VRE bacteremia,5 but clear distinction of therapeutic outcomes between the two therapies is still lacking.

    Risk Factors for VRE Bacteremia

    Patient populations at risk for VRE bacteremia include those with previous VRE colonization, hematologic malignancy, hemodialysis, neutropenia, mucositis, recent surgery, indwelling catheters, previous antibiotic therapy, use of immunosuppressive agents, and organ transplantation.6

    Toxicity Profile of Linezolid and Daptomycin

    Linezolid is known to have a number of toxicities and drug interactions with its use. Notable toxicities include thrombocytopenia, neutropenia, lactic acidosis, peripheral and optic neuropathy, and increased liver enzymes.7 Serotonin syndrome can also be seen in patients receiving concomitant serotonergic agents because linezolid exhibits low monoamine oxidase (MAO) inhibition.

    Daptomycin is associated with increases in creatine kinase (CK) levels which can result in muscle pain/weakness and rhabdomyolysis. Cases of eosinophilic pneumonia have also been reported with prolonged daptomycin use.8

    Clinical Efficacy of Linezolid and Daptomycin

    A 2015 multicenter, retrospective cohort study by Britt and colleagues compared the effectiveness of linezolid vs. daptomycin in the Veteran Affairs healthcare system. The primary outcome was clinical failure defined as a composite of 30-day all-cause mortality, microbiologic failure, and 60-day recurrence of VRE bacteremia. Linezolid was associated with a higher risk of treatment failure (risk ratio: 1.37; 95% CI 1.13-1.67; p=0.011), higher 30-day mortality rates (42.9% vs. 33.5%; RR: 1.17; 95% CI: 1.02-1.30; p=0.026), and higher microbiologic failure rates (RR: 1.10; 95% CI: 1.02-1.18; p=0.011) compared to daptomycin. No difference in 60-day VRE bacteremia recurrence was observed between the two therapies. Standard daptomycin dosing of 6 mg/kg was used in the majority of patients. Duration of treatment differed between the groups, as the linezolid group received a median treatment duration of 7 days and daptomycin group received a median treatment duration of 11 days, but the results discussed above were controlled for treatment duration.9

    A single-center, retrospective cohort study by Narayanan and colleagues evaluated the clinical effectiveness of linezolid and daptomycin in 93 patients with VRE bacteremia between 2012 and 2016. The primary outcome was clinical failure defined as a composite of 14-day mortality, microbiologic failure, or relapse of VRE bacteremia. Overall, patients treated with daptomycin had a significantly higher rate of clinical failure compared to patients treated with linezolid (74.2% vs. 46.8%, p=0.01). Individual outcomes of 14-day mortality, microbiologic failure, and relapse of VRE bacteremia were worse in patients treated with daptomycin, but not statistically significant. Daptomycin dosing remained stable throughout the patient population at a standard dose of 6 mg/kg, and the treatment duration was undisclosed for both therapies.10

    A systematic review and meta-analysis of ten retrospective studies that does not include the studies discussed previously was published in 2014 by Balli and colleagues. A total of 967 patients were identified, and the primary outcome was 30-day all-cause mortality. Patients treated with daptomycin showed significantly higher 30-day all-cause mortality (OR: 1.61; 95% CI: 1.08-2.40) and overall mortality (OR: 1.41; 95% CI: 1.06-1.89) compared to linezolid patients. The median daptomycin dose was 6 mg/kg in six studies, 5.5 mg/kg in one study, and not reported in the remaining three studies.11

    High-Dose vs. Standard-Dose Daptomycin

    Therapeutic outcome differences between high-dose daptomycin and standard-dose daptomycin in VRE bacteremia should also be addressed. A 2016 prospective cohort study compared mortality rates of VRE bacteremia treated with high-dose daptomycin (>9 mg/kg) vs. standard dose daptomycin (6 mg/kg) vs. linezolid. Use of high-dose daptomycin correlated to a significantly lower all-cause 14-day mortality compared to standard dose daptomycin (OR: 0.76; 95% CI: 0.59-0.98; p=0.03). There were no significant differences in adverse events between the high-dose and the standard-dose daptomycin groups. The study also found had lower mortality rates in the linezolid group compared to the standard-dose daptomycin group (aOR: 0.34; 95% CI: 0.14-0.79; p=0.01) and compared to all patients receiving daptomycin regardless of dose (aOR: 0.39; 95% CI: 0.18-0.85; p=0.02). The linezolid group did not show a statistically significant difference in terms of mortality when compared with high-dose daptomycin patients alone (aOR: 0.98; 95% CI: 0.14-7.03; p=0.99).12

    Discussion

    In contrast to other literature discussed, Britt and colleagues found that linezolid use was associated with higher treatment failure compared to daptomycin. This may be due to a number of reasons. The linezolid group had a higher percentage of ICU admissions compared to the daptomycin group (83.5% vs. 70.5%), indicating that linezolid may have been used in more critically ill patients. Also, a higher percentage of linezolid patients were above the age of 65 compared to daptomycin group (54.9% vs. 46.2%),12 which likely contributed to the higher mortality and microbiologic failure rates seen. As stated, both retrospective cohort studies discussed utilized a standard daptomycin dose of 6 mg/kg for a majority of their patients.

    Optimal daptomycin dosing in VRE bacteremia is critical. Daptomycin exhibits dose-dependent bactericidal activity, so the standard daptomycin dose of 6 mg/kg may not be sufficient to induce sustained bactericidal activity to eradicate enterococcal bloodstream infections. Further studies to elucidate daptomycin dose-efficacy relationships may be an important step towards suggesting high-dose daptomycin as initial therapy for VRE bacteremia.

    Conclusion

    Linezolid and daptomycin are first-line options for VRE bacteremia. Although linezolid and daptomycin have notable differences in toxicities, literature regarding their comparative clinical efficacy is somewhat conflicting. A meta-analysis suggests slightly more favorable outcomes with linezolid compared to daptomycin, but definitive conclusions are difficult to make due to the insufficient daptomycin dosing in the majority of the studies included.

    In summary, current literature favors linezolid over daptomycin in the treatment of VRE bacteremia, but clear evidence to support one agent over the other is lacking. High-dose daptomycin and linezolid have shown similar results, and both seem to be superior to standard-dose daptomycin. Choosing between high-dose daptomycin and linezolid should be individualized based on patient-specific factors such as severity of illness, concomitant infections, drug interactions, and tolerability to therapy.

    References

    1. O’Driscoll T, Crank CW. Vancomycin-resistant enterococcal infections: epidemiology, clinical manifestations, and optimal management. Infect Drug Resist. 2015; 8:217-30.
    2. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States. 2013; https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. Accessed July 6th, 2019.
    3. Cheah AL, Spelman T, Liew D et al. Enterococcal bacteraemia: factors influencing mortality, length of stay and costs of hospitalization. Clin Microbiol Infect. 2013; 19(4):E181-9.
    4. Prematunge C. VRE and VSE bacteremia outcomes in the era of effective VRE therapy: A systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2016; 37(1):26-35.
    5. Memel LA, Allon M, Bouza E et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009; 49:1-45.
    6. Patel R. Clinical impact of vancomycin-resistant enterococci. J Antimicrob Chemother. 2003; 51:Suppl 3:iii13-21.
    7. Zyvox® [package insert]. New York, NY: Pfizer Company Inc.; 2008.
    8. Cubicin® [package insert]. Whitehouse Station, NJ: Merck & Co. Inc.; 2003.
    9. Britt NS, Potter EM, Patel N et al. Comparison of the effectiveness and safety of linezolid and daptomycin in vancomycin-resistant enterococcal bloodstream infection: A national cohort study of Veterans Affairs patients. Clin Infect Dis. 2015; 61(6):871-8.
    10. Narayanan N, Raj R, Vaidya P et al. Comparison of linezolid and daptomycin for the treatment of vancomycin-resistant enterococcal bacteremia. Ther Adv Infect Dis. 2019; 13(6):1-8.
    11. Balli EP, Venetis CA, Miyakis S. Systematic review and meta-analysis of linezolid versus daptomycin for treatment of vancomycin-resistant enterococcal bacteremia. Antimicrob Agents Chemother. 2014; 58(2):734-9.
    12. Chuang YC, Lin HY, Chen PY et al. Daptomycin versus linezolid for the treatment of vancomycin-resistant enterococcal bacteremia: implications of daptomycin dose. 2016; 22(10):890.


  • 14 Nov 2019 12:29 PM | MSHP Office (Administrator)

    Authors: Ellisa Zhang, PharmD Candidate 2020 and April Pottebaum, PharmD, BCPS

    Hepatitis B Risk

    Based on a national health survey, an estimated 850,000 people are living with hepatitis B in the United States.1 However, this number could be an underestimate since studies evaluating migration data and prevalence of hepatitis B in foreign countries estimate that this number could be as high as 2.2 million. 1 The hepatitis B virus (HBV) is a DNA virus that replicates in the liver and can progress to a chronic infection that leads to an increased risk of liver cirrhosis and hepatocellular carcinoma.1,2 HBV is transmitted through infected blood and body fluids via percutaneous or mucosal contact.1 It can also remain infectious on non-living surfaces in the environment for at least 7 days. Thus, patients on dialysis are especially at risk for acquiring HBV due to increased exposure to blood with frequent dialysis treatments as well as use of shared dialysis equipment.2

    Patients with end-stage renal disease (ESRD) are more susceptible to infection due to a weakening of the immune system secondary to uremia.3 Production of T-cells is decreased and alterations of costimulatory molecules CD80 and CD86 impair the activity of antigen-presenting cells in this patient population.This suppresses the adaptive immune response, leading to a higher rate of infection, a lower response rate to vaccinations, and a shorter duration of seroprotection against antigens.3 Fifty to seventy percent of dialysis patients respond to the hepatitis B vaccine, but only 40% will maintain protection against HBV three years after their vaccination series, as compared to initial response rates of > 90% in healthy adults aged < 40 years and 75% in adults aged 60 years.1,4 Studies evaluating causes of reduced seroconversion in ESRD patients show conflicting results, likely because these studies have small sample sizes and different methodologies for administering the hepatitis B vaccines.4-6 Since patients vaccinated in earlier stages of renal disease showed higher rates of seroconversion, it is advisable to start hepatitis B vaccinations before patients become dialysis dependent.7,8

    Current Hepatitis B Vaccine Recommendations

    Updated guidance on use of HBV vaccines in adults on hemodialysis was provided by ACIP in January 2018. Due to the increased risk of exposure to HBV, serological testing is recommended before vaccination for patients receiving hemodialysis.1 Testing includes the hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc). Anti-HBs levels >10 mIU/mL generally indicate seroprotection against HBV infection, but the cutoff values could differ based on the assay used. While testing is not required for vaccination, it can reduce costs by avoiding vaccination in persons who are already immune. In settings where testing is not feasible, vaccination should continue as administration of the vaccine to individuals who are immune due to acute or chronic HBV infection or previous vaccination does not increase the risk for adverse events.1

    For patients > 20 years old on dialysis, either high-dose Engerix-B® (40 mcg) or high-dose Recombivax HB® (40 mcg) given IM is recommended.1 Engerix-B® is a 4-dose series given at months 0, 1, 2, and 6 while Recombivax HB® is a 3-dose series given at months 0, 1, and 6. If the vaccination series is interrupted, it does not need to be restarted. If the second dose is delayed, it should be administered as soon as possible, and then the third dose must be separated from the second dose by at least 8 weeks. If the third dose is delayed, it should be administered as soon as possible.1 The series should be completed with vaccines from the same manufacturer when possible.9

    Although serologic testing for immunity is not routinely performed after vaccination of most individuals, anti-HBs levels should be assessed 1 to 2 months after completion of the vaccination series in dialysis patients.1 For most assays, if the level is >10 mIU/mL, then the patient is considered immune and does not need further vaccinations. However, if the level is <10 mIU/mL, then the patient should complete another full vaccination series, and another anti-HBs titer should be checked 1 to 2 months after this revaccination. If there is still no serologic response, then a test for HBsAg is recommended to determine infection status. A positive HBsAg indicates HBV infection, so the patient would need to be educated about strategies to prevent the spread of infection. If the HBsAg is negative, the patient is still susceptible to HBV infection, so he or she should be counseled on how to prevent infection and the importance of receiving hepatitis B immune globulin (HBIG) if exposed to infected blood.1

    Annual anti-HBs testing is recommended in dialysis patients to determine if a booster dose of hepatitis B vaccine is needed. Patients should receive a booster dose of hepatitis B vaccine if the anti-HBs level falls to <10 mIU/mL. Testing to assess the efficacy of the booster dose is not necessary.1 Figure 1 provides a summary of these recommendations.

    New Vaccine on the Market

    Heplisav-BTM by Dynavax is a newer HBV vaccine that was FDA-approved in November 2017 for adults 18 years and older. Heplisav-B™ is an attractive alternative to Engerix-B® or Recombivax HB® for hepatitis B vaccination due to a more convenient dosing schedule as well as better seroprotection.10 It is a 2-dose series, with doses administered IM at least one month apart. While the other HBV vaccines use aluminum hydroxide as an adjuvant, Heplisav-BTM uses a novel adjuvant cytosine phosphoguanine oligonucleotide (CpG1018). CpG1018 is synthesized from bacterial DNA and helps stimulate the immune system by activating the toll-like receptor 9 (TLR-9) pathway.10

    The clinical trials that led to approval of Heplisav-B™ were phase 3 noninferiority studies which compared response rates of Heplisav-BTM to Engerix-B®.11-13 In a study of healthy patients aged 18-55 years, Heplisav-B™ was shown to provide significantly higher rates of seroprotection as compared to Engerix-B® (97.9% vs 81.1%).11 Another study in healthy adults aged 40-70 years also found a significantly higher response to Heplisav-B™ as compared with Engerix-B® (94.8% vs 72.8%).12 Similar results were also observed in a study of patients with type 2 diabetes.13 While Heplisav-BTM did demonstrate increased efficacy as compared to Engerix-B® in each of these studies, it also caused more injection-site reactions.11-13 Despite these promising findings, the studies did not include patients on dialysis, so use of Heplisav-B™ cannot be routinely recommended in this patient population until more data is available.14 A study is currently enrolling patients on hemodialysis to assess the safety and efficacy of Heplisav-BTM with an estimated completion date of April 2021.15

    Even with the potential for improved immunogenicity with Heplisav-B™, ACIP still recommends testing for anti-HBs to determine vaccine response in hemodialysis patients and other populations at risk for HBV infection.14 Since there is limited data about switching between Heplisav-BTM and the other hepatitis B vaccines (i.e. Engerix-B® or Recombivax HB®), these vaccines should not be interchanged. If a patient receives one dose of Heplisav-BTM and one dose of another hepatitis B vaccine, then the vaccination series should be completed with a total of three vaccine doses.14

    Conclusion

    Patients on dialysis are at higher risk for HBV infection compared to the general population due to the nature of dialysis procedures requiring frequent vascular access and a suppressed immune system secondary to uremia. Furthermore, patients on dialysis have lower response rates to hepatitis B vaccines and decreased ability to maintain seroprotection against HBV. It is essential to ensure patients on dialysis are vaccinated appropriately and monitored annually for seroprotection to the hepatitis B virus. While alternative strategies for hepatitis B vaccination are needed to combat this problem and a newer HBV vaccine is showing promise for improved immunogenicity, further studies are needed to fully assess efficacy in this patient population. ACIP offers the most current evidence-based recommendations for vaccination to prevent HBV infection.

    Figure 1.

    Current Recommendations on the Prevention of HBV Infection in Patients Undergoing Hemodialysis


    References

    1. Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus infection in the United States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018;67(1):1–31.
    2. Yousaf F, Gandham S, Galler M, Spinowitz, Charytan C. Systematic review of the efficacy and safety of intradermal versus intramuscular hepatitis B vaccination in end-stage renal disease population unresponsive to primary vaccination series. Ren Fail. 2015;37(7):1080-88.
    3. Kato S, Chmielewski, Honda H, et al. Aspects of immune dysfunction in end-stage renal disease. CJASN. 2008;3(5):1526-33.
    4. Saco TV, Strauss AT, Ledford DK. Hepatitis B vaccine nonresponders: possible mechanisms and solutions. Ann Allergy Asthma Immunol. 2018;121:320-7.
    5. Asan A, Demirhan H, Sorkun HC, et al. Factors affecting responsiveness to hepatitis B immunization in dialysis patients. Int Urol Nephrol. 2017;49:1845-50.
    6. Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulus V, Stefanidis I. Factors affecting effectiveness of vaccination against hepatitis B virus in hemodialysis patients. World J Gastroenterol. 2014;20(34):12018-25.
    7. Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission in the United States, recommendations of the Advisory Committee on Immunization Practices (ACIP) part II: immunization of adults. MMWR Recomm Rep. 2006;55(RR16):1-25.
    8. Daroza G, Loewen A, Djurdjev O, et al. Stage of chronic kidney disease predicts seroconversion after hepatitis B immunization: earlier is better. Am J Kidney Dis. 2003;42(6):1184-92.
    9. Ezeanolue E, Harriman K, Hunter P, Kroger A, Pellegrini C. General best practice guidelines for immunization. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf. Accessed July 14, 2019.
    10. JAMA. A two-dose hepatitis B vaccine for adults (Heplisav-B) JAMA. 2018;319(8):822-23.
    11. Halperin SA, Ward B, Cooper C, et al. Comparison of safety and immunogenicity of two doses of investigational hepatitis B virus surface antigen co-administered with an immunostimulatory phosphorothioate oligodeoxyribonucleotide and three doses of a licensed hepatitis B vaccine in healthy adults 18-55 years of age. Vaccine. 2012;30(15):2556-63.
    12. Heyward WL, Kyle M, Blumenau J, et al. Immunogenicity and safety of an investigational hepatitis B vaccine with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared to a licensed hepatitis B vaccine in healthy adults 40-70 years of age. Vaccine. 2013; 31(46):5300-5.
    13. Jackson S, Lentino J, Kopp J, et al. Immunogenicity of a two-dose investigational hepatitis B vaccine, HBsAg-1018, using a toll-like receptor 9 agonist adjuvant compared with a licensed hepatitis B vaccine in adults. Vaccine. 2018;36(5):668-74.
    14. Schillie S, Harris A, Link-Gelles R, Romero J, Ward J, Nelson N. Recommendations of the advisory committee on immunization practices for use of a hepatitis B Vaccine with a novel adjuvant. MMWR Morb Mortal Wkly Rep. 2018;67:455–58.
    15. NIH. HEPLISAV-B® in adults with end-stage renal disease (ESRD) undergoing hemodialysis. ClinicalTrials website. https://clinicaltrials.gov/ct2/show/NCT03934736. May 2, 2019. Accessed June 28, 2019.  


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