Authors: Peggy Pace, RPh, BCGP, BCPS and Chelsea Meczkowski, PharmD
Christian Hospital- St. Louis
HMG CoA reductase inhibitors, or “statins”, soon became the mainstay of treatment for secondary prevention in atherosclerotic cardiovascular disease (ASCVD) after their introduction to the prescription market in 1987. Their benefit has been primarily attributed to the reduction of blood cholesterol, specifically the LDL-C component, though other mechanisms have been proposed and are being investigated.1 After the publication in 2008 of Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), primary prevention was added as an indication for the first time.2
As the US population ages, statin use is expected to increase among elders. In fact, from 1999-2011, statin use in patients older than 80 years increased nearly four-fold.3 This article will evaluate current evidence on the safety and effectiveness of these agents in patients > 75 years when used for primary prevention. Their use for secondary prevention will not be evaluated.
There are several tools available online to estimate risk of ASCVD in patients without known heart or vascular disease. Commonly used tools are the ACC/AHA ASCVD Risk Estimator Plus and the Pooled Cohort Equations to estimate 10-year risk for ASCVD events.4,5 The outcome of these estimators is heavily dependent on age, such that all patients > 75 are advised to start statin therapy if LDL-C is 70 mg/dL or greater. A caveat is that these tools should not be used to seek therapy advice for patients older than 79 years. The American Board of Internal Medicine acknowledges these estimators’ weakness for use in the elderly with advice at “Choosing Wisely”, a campaign aimed at reduction of medication, testing, and procedure overuse. The advice to older patients states in part: “Many older adults have high cholesterol. Their doctors usually prescribe statins to prevent heart disease. But for older people, there is no clear evidence that high cholesterol leads to heart disease or death. In fact, some studies show the opposite—that older people with the lowest cholesterol levels have the highest risk of death.”6 Similarly, the American College of Cardiology 2018 Guideline on the Management of Blood Cholesterol says that for patients older than 75, statins should be started only after a clinical assessment and a discussion of risk.7 Risk for ASCVD increases with age, so why the caution when adding a statin to drug regimens of older patients?
Additions to medication regimens should be made when benefits clearly outweigh risks, and only after discussion with the patient and/or their caregiver. Reasons for caution when adding a statin include comorbidities, complicating existing drug regimens, increased expense, the potential for drug interactions with existing medications, and of course potential side effects such as myopathy, impaired cognition, and new onset diabetes.
The likelihood of drug interactions is increased in elders because the oxidative capacity of the liver decreases with age. Any medications metabolized by oxidation are more likely to accumulate.8 Statins are metabolized to varying degrees by cytochrome P450 (CYP) enzymes, an oxidative pathway.9 Medications that induce, inhibit, or compete for the CYP enzymes will require careful monitoring. These interactions could result in reduced levels/ineffectiveness (i.e., atorvastatin + rifampin) or increased levels/side effects (i.e., simvastatin + verapamil) of the statin.10,11
Myopathy, a known side effect of statin therapy, can lead to sedentary behavior resulting in increased frailty and falls. This side effect is hotly debated among experts but remains a complaint in about 1 in 5 patients.12 Avoiding movement due to muscle pain can worsen frailty and lead to weakness. A fall can be disastrous in an elder, especially if it results in a fracture requiring surgery. In addition to surgical risks, post-op complications, delayed healing, and months of physical therapy could result in loss of independence.
Cognitive impairment has been recognized with these agents, though the mechanism is not understood. Statins are thought to be protective of cognition in some conditions, but cause impairment in other patients.13 If it occurs, it is generally reversible with drug discontinuation.13 Cognitive side effects could easily be overlooked or attributed to something else, and elders themselves may be unwilling to report these symptoms.
The risk of new onset diabetes is increased with the use of statins.14 This may take years to manifest, so it may seem to be less of a concern in a person with a limited life expectancy. However, CDC reports that a person who has survived to age 75 in 2016 is expected to live on average another 12.3 years.15
Risk vs. Benefits: the Actual Numbers
The World Health Organization has requested that study results be reported in Absolute Risk Reduction (ARR) or Number Needed to Treat (NNT), rather than Relative Risk Reduction (RRR), as these convey a clearer picture of expected benefit.16 This has mostly been ignored, making it difficult to determine if a perceived benefit is worth the associated risks.17 Relative risk gives risk of occurrence of an event in the experimental group relative to the control group. Absolute risk tells us the number of events in the experimental group versus the number in the control group in absolute terms. The number needed to treat tells us how many patients have to receive a treatment for one patient to benefit.
For example, if the risk of developing a disease or condition is 20% and an intervention can reduce that risk to 15%, it is correct to say the intervention showed a RRR of 25% [(20%-15%)/20%], which sounds more significant than the ARR of 5% (20%-15%). The NNT is the inverse of the ARR, or 1/0.5=20 patients need to be treated for one to realize a benefit in this example.18 The more impressive sounding 20% RRR might persuade patients and providers to accept the risks associated with treatment, while the 5% ARR might not offer a benefit they think is worth those risks. For this reason, it is helpful to convert reported RRR to ARR or NNT for patients up front when discussing whether to start a new therapy.
JUPITER was said to prove the benefit of taking rosuvastatin for primary prevention, reporting a 43% reduction of risk, according to the trial authors.2 How did they arrive at these figures? In the placebo group the rate of a negative outcome was 1.36% while in the rosuvastatin group the rate was 0.77%. The ARR was 1.36%-0.77%=0.59%.2 Stated as RRR, this figure is (1.36-0.77)/1.36 or 43%.2 So the ARR is less than 1%, but the over 40% RRR was the figure the study authors chose to report, and what readers remember. The NNT in JUPITER is 1/0.0059= 170 patients for one year for one patient to realize a benefit.
Pravastatin in elderly individuals at risk of vascular disease (PROSPER), which enrolled patients aged 70-82, reported that the primary composite endpoint at 3 years (CHD-related death, nonfatal MI, and stroke) in the placebo group was 16.2% vs. 14.1% in the pravastatin group.19 This is an ARR = 2.1%, but is reported as a relative risk reduction of 13%.19 This corresponds to 48 patients treated for 3 years for one patient to realize a benefit. PROSPER was not exclusively a primary prevention trial, but analysis of the primary prevention subgroup showed no benefit with the statin.19
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT-LLT) trial concluded there was no significant difference in outcomes when pravastatin vs. placebo was used for primary prevention in adults older than 65.20 The Third Heart Outcomes Prevention Evaluation(HOPE-3) trial also looked at statin use for primary prevention.21 Refreshingly, HOPE-3 reported the ARR and NNT in the published trial. The ARR was 1.1%, corresponding to 91 patients needing to be treated for 5.6 years for one patient to benefit.21 These stastistics are summarized in the table below.
Studies Evaluating Statin Use for Primary Prevention in the Elderly
A new study, Statin therapy for reducing events in the elderly (STAREE) is currently recruiting with an estimated study completion in 2033.22 Until then, we have precious few trials that include the elderly to assist in making decisions on whether to start or continue statins in patients over 75 with no evidence of ASCVD.
ASCVD increases with age so it seems reasonable that lipid lowering therapy provides a benefit in older adults, but this assumption does not always hold up to scrutiny. There are numerous other risk reduction strategies with proven benefit that should be considered besides reducing cholesterol, such as blood pressure control and lifestyle modifications.23 Shared decision making should be used to elicit patients’ values and goals of care to be sure therapies are aligned with expressed wishes.24 In addition, factors such as life expectancy, time to benefit, current comorbidities, costs, and risks of therapy must be included in frank discussions with patients and/or caregivers before agreeing on the best course of treatment for older adults.
Author: Hunter Ragan, PharmD Candidate 2020; SIUE School of PharmacyMentor: Sarah Cook PharmD, BCPS; SSM Health St. Joseph Hospital – St. Charles
Cardiovascular Disease (CVD) is the leading cause of death for adults in the United States, with approximately 610,000 deaths due to CVD per year.1 Patients with hyperlipidemia are at roughly twice the risk of developing CVD compared to those with normal cholesterol levels.2 Over 95 million adults aged 20 or older in the United States have hyperlipidemia with total cholesterol greater than 200 mg/dL.3
Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are the newest class of cholesterol-lowering medications and have been shown to reduce LDL-C by up to 70%. There are currently two PCSK9 inhibitors approved by the FDA: alirocumab (Praluent) and evolocumab (Repatha). They are fully human monoclonal antibodies that bind in a 1:1 ratio to circulating PCSK9, which normally binds to low-density lipoprotein receptors (LDLR) on the surface of hepatocytes and promotes their degradation. LDLR are the primary receptors responsible for removing LDL-C from the blood. Thus, PCSK9 inhibitors increase clearance of LDL-C from the blood by increasing the number of LDLR on hepatocytes.4,5
Alirocumab was the first FDA-approved PCSK9 inhibitor in July 2015 with an indication of primary hyperlipidemia; an additional indication of secondary prevention of myocardial infarction (MI), stroke, and unstable angina (UA) requiring hospitalization was recently added in April 2019.6 The ODYSSEY Phase III Program which led to alirocumab’s initial FDA approval consisted of multiple studies enrolling more than 23,000 patients. These studies showed statistically significant improvement in LDL-C levels, but CVD benefit was not assessed in these trials. The ODYSSEY OUTCOMES trial was undertaken to assess the impact of alirocumab on CVD.7
The ODYSSEY OUTCOMES trial was a multicenter, randomized, double-blind, placebo-controlled trial that consisted of more than 18,000 patients in 57 countries. Eligible patients were 40 years of age or older with elevated LDL-C (≥70 mg/dL) or elevated non-HDL-C (≥100 mg/dL) despite high-intensity or maximally tolerated statin therapy that experienced acute coronary syndrome (ACS) within 1-12 months prior to enrollment. The primary end point was a composite of death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, and UA requiring hospitalization. The targeted LDL-C value was 25-50 mg/dL and median follow up was 2.8 years. Baseline median LDL-C was 87 mg/dL in both treatment and placebo groups, and alirocumab resulted in 54.7% lower LDL-C at 2 years compared to placebo. Alirocumab also resulted in a 15% reduction in the composite primary endpoint compared to placebo (95% CI 0.78-0.93; p=0.0003). Additionally, alirocumab was associated with a 15% reduction in the secondary endpoint of all-cause mortality compared to placebo, with an incidence of 3.5% in the alirocumab group and 4.1% in the placebo group (95% CI 0.73-0.98; p=0.026). However, the difference in mortality due to coronary heart disease alone was not found to be statistically significant. Subgroup analysis of the ODYSSEY OUTCOMES trial found that patients with baseline LDL-C values higher than 100 mg/dL experienced a greater benefit with alirocumab. Additionally, patients achieving LDL-C levels of approximately 30 mg/dL at 4 months of treatment experienced lower all-cause mortality rates.8,9
Alirocumab’s most common adverse effect seen in clinical trials was injection site reactions; flu-like symptoms, cough, and myalgias were also reported (all at rates < 10%). Neutralizing antidrug antibodies to alirocumab were noted in clinical trials at a rate of approximately 1%, with even fewer patients having loss of efficacy due to their presence.10 A safety analysis of 5 placebo-controlled trials studying alirocumab found no statistical difference in new-onset of diabetes or worsening of diabetes, which was consistent with results seen in ODYSSEY OUTCOMES. The most common side effects noted in this study were nasopharyngitis, upper respiratory infections, and injection site reactions.11
Evolocumab was approved in August 2015 for primary hyperlipidemia, homozygous familial hypercholesterolemia (HoFH), and heterozygous familial hypercholesterolemia (HeFH); an additional indication of secondary risk reduction after MI, stroke, and coronary revascularization was approved in December 2017.12 Similar to the phase III trials leading to alirocumab’s initial FDA approval, studies of evolocumab showed significant reduction of LDL-C (approximately 54-77% reduction at 12 weeks compared to placebo) but did not assess clinical endpoints related directly to CVD morbidity or mortality.13 The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial assessed the impact of evolocumab on CVD, and was the first study to look at the impact of PCSK9 inhibitors on CVD outcomes.
The FOURIER trial was a multinational, randomized, double-blind, placebo-controlled trial involving over 27,000 patients in 49 countries. Eligible patients were between 40-85 years of age with clinically evident ASCVD with elevated LDL-C (≥70 mg/dL) or elevated non-HDL-C (≥100 mg/dL) despite maximally tolerated statin therapy (at least atorvastatin 20 mg daily or its equivalent) with or without ezetimibe. Patients with prevalent diabetes were excluded at the start of the trial. The primary endpoint was the composite of CV death, MI, stroke, hospitalization for UA, or coronary revascularization. After a median follow-up of 2.2 years, the primary endpoint was experienced in 9.8% of the evolocumab group and in 11.3% of the placebo group (HR 0.85; 95%CI 0.79-0.92). No significant difference in all-cause mortality or mortality due to coronary heart disease alone was noted. Both treatment and placebo groups had a median LCL-C of 92 mg/dL at baseline, and at 48 weeks, LDL-C was reduced to a median of 30 mg/dL in the evolocumab group.14 A secondary analysis of the FOURIER trial found that event rates for the primary outcome were lowest in patients who achieved the lowest LDL-C and highest in those with the highest LDL-C.15 The authors concluded that high-risk CVD patients may benefit from lowering LDL-C levels below current goals.14
The most commonly reported adverse effect from evolocumab is nasopharyngitis; additional side effects include injection site reactions, diabetes, and flu-like symptoms, and rarely neurocognitive effects.10 In the FOURIER trial, the number of patients with new-onset diabetes, neurocognitive effects, and muscle-related events were numerically higher, but these were not statistically significant.14 Additionally, an analysis of multiple placebo-controlled trials of evolocumab did not find the presence of anti-evolocumab antibodies in any of the trials analyzed.16
Current Guideline Recommendations
The 2018 Guideline on the Management of Blood Cholesterol from the American Heart Association (AHA), American College of Cardiology (ACC), and others recommend high-intensity (or maximally tolerated) statin therapy as first line medication therapy in patients with clinical ASCVD (Class I recommendation). In patients with LCL-C ≥ 70 mg/dL despite statin therapy, the addition of ezetimibe is reasonable (Class IIa recommendation for very high risk individuals, Class IIb recommendation for not very high risk individuals). If LDL-C ≥ 70 mg/dL or non-HDL-C ≥ 100 mg/dL despite both therapies, a PCSK9 inhibitor may be reasonable in patients at very high risk (Class IIa recommendation). PCSK9 inhibitors can also be considered prior to ezetimibe, but this is not preferred (Class I recommendation). Very high risk individuals have multiple ASCVD events or 1 ASCVD event plus multiple other high risk conditions. PCSK9 inhibitors should also be considered in patients with HeFH when LDL-C ≥ 100 mg/dL despite treatment with a maximally tolerated statin and ezetimibe (Class IIb recommendation) as well as in patients with baseline LCL-C ≥ 220 mg/dL with an LDL-C ≥ 130 mg/dL despite being on a maximally tolerated statin and ezetimibe (Class IIb recommendation). These guidelines do acknowledge that the cost-effectiveness of PCSK9 inhibitors is not well defined, particularly in patients without clinical ASCVD using PCSK9 inhibitors for primary prevention of CVD.17
The 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease only mention the use of statins for cholesterol management based on a patient’s ASCVD risk score and risk enhancers such as family history, LDL-C > 160 mg/dL, chronic kidney disease, and others.18 However, these recommendations may change in the future based on the results of the VESALIUS-CV trial which was announced in March 2019. This study will enroll a minimum of 13,000 patients from various countries and will evaluate primary prevention of CV events in patients with high CVD risk but no prior MI or stroke. It will last a minimum of four years or until a sufficient number of patients experience the primary composite outcome of time to CVD death, MI, or ischemic stroke. It will also evaluate time to CVD death, MI, ischemic stroke, or any ischemia driven arterial revascularization.19
Currently, PCSK9 inhibitors’ primary place in therapy is for secondary prevention of CVD in patients with LDL-C ≥ 70 mg/dL or non-HDL-C ≥ 100 mg/dL despite a maximally tolerated statin and ezetimibe therapy and for LDL-C lowering in patients with severe primary hyperlipidemia. The FOURIER and ODYSSEY trials have shown promise with their use in preventing secondary ASCVD events. Alirocumab also showed a decrease in all-cause mortality while evolocumab did not, which could potentially be due to the higher-risk population in ODYSSEY OUTCOMES compared to FOURIER. Previous phase III trials of both PCSK9 inhibitors have already established their effectiveness in lowering LDL-C in patients with primary hyperlipidemia, but further trials are needed to establish their effectiveness for primary prevention of CVD. Further research is also needed to establish the ideal LDL-C target.
Overall, PCSK9 inhibitor’s clinical benefits related to lowering LDL-C and secondary prevention of CVD are evident, and their adverse events noted in clinical trials are minimal. Long-term safety data is remains unknown due to their novelty. Additionally, cost concerns and cost-effectiveness are still unclear, although the manufacturers have reduced pricing since their initial release to promote their use and garner more insurance approval. Manufacturer websites can be consulted to find further information on payment assistance options that are available.
Impact of Cardiovascular Disease
In the study “Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial”, it was found that aspirin was no more effective in preventing adverse cardiovascular events among moderate-risk patients than placebo.
ASPREE5The ”Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly”, it was found that there was a much higher risk of major hemorrhage in patients who were 70 years or older taking aspirin for primary prevention of CVD, and did not result in significantly lower risk of CVD than placebo.
^= Higher ASCVD risk2:
¥ = increased bleeding risk2:Those considered an increased risk of bleeding include but are not limited to: a history of previous gastrointestinal bleeding or peptic ulcer disease or bleeding at other sites, age >70 years, thrombocytopenia, coagulopathy, CKD, and concurrent use of other medications that increase bleeding risk, such as nonsteroidal anti-inflammatory drugs, steroids, direct oral anticoagulants, and warfarin
Both pharmacological and nonpharmacological methods can be utilized to combat CVD depending on the patient. It’s our roles as pharmacists to not only understand the current guidelines in the primary prevention of CVD, but also track the progress of these guidelines in the future. By staying on top of the current guidelines we can ensure the best care possible for the patients we serve.
Author: Diane McClaskey, RPh, BCPS; UMKC School of Pharmacy at MSU
Today we are going to discuss the latest addition to our alphabet soup, EPA! An EPA is an entrustable professional activity, and are utilized across Schools and Colleges of Pharmacy to ensure consistency in new pharmacy graduates to perform core tasks. Please allow me to explain further.
In 2016, the American Association of Colleges of Pharmacy tasked their Academic Affairs Committee to identify activities that all pharmacy graduates should be able to perform without direct supervision upon graduation from an accredited college/school of pharmacy. To be included, each EPA was evaluated to ensure:
These EPAs serve as a baseline for all types of practice settings, not a ceiling, and are independent of practice setting. For each element and supporting task, three key assumptions must be present. These include: professionalism, self-awareness, and communication.
Let’s take a deeper look into the core EPA statements that describe what it is to be ‘practice-ready’ and ‘team-ready’. First, the statements were categorized by the role of the pharmacist within the activity. The six roles (domains) include:
With respect to the patient care provider domain, the activities encompass the Pharmacists’ Patient Care Process (we like to call it ‘The Wheel’!).
Example supporting tasks within this role include:
The next EPA is the ability for a new pharmacy graduate to collaborate as a member of an interprofessional team. Example supporting tasks include: communicating a patient’s medication-related problem(s) to another health professional, contributing medication-related expertise to the team’s work, and using consensus building strategies to develop a shared plan of action.
For population health promoter domain, what do you think of right away? Probably vaccines and the impact that pharmacists have, and you are correct! Other EPAs within this domain include: screening assessments, minimizing adverse drug events and medication errors, and maximizing appropriate use of medications.
The ability to educate patients and other healthcare professionals regarding the appropriate use of medications is identified as one of the EPAs included in the information master role of a new pharmacy graduate. The ability to utilize evidence-based information is also contained within the information master domain.
The next domain is that of a practice manager. The EPAs identified within this role include the ability to fulfill a medication order, and to oversee the pharmacy operations for an assigned work shift. Supporting tasks can include:
The last role that new pharmacy graduates should possess is that of developing a continuous professional development plan. An example supporting task is performing a self-evaluation to identify professional strengths and weaknesses.
As you can see, EPAs are daily pharmacist functions that any one of us complete routinely, and can provide you guidance as you precept students on rotations. Knowing and understanding of these EPAs and suggested tasks will allow for students to have multiple and repeated opportunities to practice and achieve competency.
Adham Mohamed, PharmD and Timothy Berry, PharmD, BCPS
Saint Luke’s Hospital of Kansas City
Piperacillin-tazobactam (PTZ) is a combination of an expanded spectrum anti-pseudomonal penicillin and a β-lactamase inhibitor which protects piperacillin from degradation by β-lactamases produced by methicillin-sensitive Staphylococcus aureus, Haemophilus influenzae, and Morganella catarrhalis.1,2
PTZ is approved by the Food and Drug Administration (FDA) for the treatment of intra-abdominal infections (IAI), uncomplicated and complicated skin and soft tissue infections (SSTI), female pelvic infections, community-acquired pneumonia, and nosocomial pneumonia.3
PTZ provides coverage against a wide variety of gram-positive and gram-negative organisms (table 1).3 PTZ also exerts activity against some anaerobic bacteria (e.g. Bacteroides fragilis).3
The 2016 Infectious Diseases Society of America (IDSA) guidelines for the treatment of hospital-acquired pneumonia (HAP)and ventilator-associated pneumonia (VAP) suggest the use of PTZ in combination with non-β-lactam antipseudomonal agents for the treatment of VAP and suggested the use of PTZ for the treatment of HAP.4 The 2014 IDSA guidelines for the treatment of SSTI recommended PTZ in combination with anti-methicillin-resistant S. aureus (MRSA) antimicrobials for the empiric treatment of severe infections such as; necrotizing fasciitis, clostridial gas gangrene or myonecrosis, SSTIs during an episode of fever and neutropenia and cellulitis in severely compromised patients.5 The 2010 IDSA guidelines for the treatment of IAI also suggested the use of PTZ for the treatment of high-risk community acquired IAI or healthcare-associated IAI.6 The aforementioned HAP/VAP and SSTI guidelines suggested PTZ among a variety of other agents, however, PTZ always appears on the top of the list of suggested empiric antimicrobials.4,5
Based on the factors mentioned earlier, PTZ became a very common empiric first-line antimicrobial agent for critically ill patients. A 2011 survey of 183 US hospitals looking at the prevalence of antimicrobial medication use in acute care hospitals found that PTZ was the second most common antibiotic used to treat infections in critically ill patients, making up 25.6% of all antimicrobial medications given. This survey also showed that PTZ is one of the top antimicrobial used to treat infection in non-critically ill patients.7 The survey also showed that vancomycin is the most commonly used antimicrobial in critically ill patients, which reflects a widespread practice of prescribing a combination of PTZ and vancomycin empirically to treat infections in critically ill patients.7
Critical care clinicians often prefer using PTZ as a first line empiric antibiotic as it provides broad coverage against gram-positive and gram-negative organisms, especially in patients with risk factors for multi-drug resistant organisms.
Recently, there has been a growing concern with the empiric use of PTZ as a first-line antimicrobial for the treatment of infections in critically ill patients. These concerns include the increased incidence of extended-spectrum β -lactamase (ESBL)-producing bacteria and PTZ’s inferiority in treating infections caused by these bacteria and the risk of acute kidney injury (AKI) with PTZ and vancomycin combination therapy.
PTZ and ESBL-Producing Bacteria
Antibiotic-resistant infections are a growing challenge; causing two million infections per year which results in 23,000 deaths per year.8 The Center for Disease Control (CDC) categorizes ESBL-producing Enterobacteriaceae as a serious threat.8 ESBL-producing Enterobacteriaceae cause 26,000 infections per year, which results in 1700 deaths.8 Infections with ESBL-producing Enterobacteriaceae have a 57% higher mortality rate and increased healthcare cost by 40,000 USD.8 The prevalence of ESBL-producing bacteria is rising worldwide.9 CTX-M, TEM, and SHV are the major ESBL enzymes, and CTX-M is the most prevalent type globaly.9,10
As we see an increase in the incidence of infections caused by ESBL-producing bacteria in critically ill patients, PTZ may not be the best option to treat ESBL-producing bacteria, namely bacteremia. Carbapenems remain the drug of choice to treat ESBL-producing bacteria.
A retrospective cohort study in 37 hospitals from 12 countries compared β-lactam/β-lactamase inhibitor combinations (BLBLIs) to carbapenems in patients with clinically significant bloodstream infection due to ESBL or carbapenemase-producing Enterobacteriaceae.11 The study had two cohorts; empiric therapy cohort (ETC) and targeted therapy cohort (TTC). The ETC had 170 patients in BLBLIs group, and 195 patients in the carbapenem group with 65% in the BLBLIs group receiving PTZ. In the TTC, 92 patients received BLBLIs, while 509 patients received carbapenem; 83% of the patients in the BLBLI group received PTZ.11
There was no difference in the primary outcome of 30 days mortality in both cohorts In the ETC, the BLBLI group had 17.6% mortality compared to 20% in the carbapenem group (P = 0.6) and in the TTC, mortality in BLBLI group was 13.9% vs. 9.8% in the carbapenem group (P = 0.28).11
Ng et al. conducted a single-center, retrospective, cohort study that included 151 patients with E. coli and K. pneumoniae ESBL bacteremia. There were 94 patients in the PTZ group and 57 patients in the carbapenem group. The authors did not find a difference in the primary endpoint of 30 days mortality between the two groups (PTZ 30.9% vs. carbapenem 29.8%, P = 0.89). The authors observed a statistically significant higher incidence of multi-drug resistant and fungal infections in the carbapenem arm (PTZ 7.4% vs. carbapenem 24.6%, P<0.01) and relapsed bacteremia (PTZ 3.2 % vs. carbapenem 15.8%, P = 0.05).12
A retrospective study by Tamma et al. included 213 patients with ESBL bacteremia who received empiric PTZ or a carbapenem and received carbapenem as definitive therapy after blood cultures. In this study, the empiric PTZ group had a higher 14 day mortality after the first positive blood culture with empiric PTZ (17% vs. 8%). After adjusting for covariates, empiric PTZ had a 1.92 times increased risk of death (95% CI, 1.07–3.45; P = 0.03).13
Recently the MERINO trial was published, which was the first randomized control trial to compare PTZ vs. meropenem as a definitive therapy of bloodstream infection caused by ESBL-producing E. coli or Klebsiella spp resistant to ceftriaxone but susceptible to PTZ. The MERINO trial was a multicenter, open-label, parallel group, randomized clinical trial. It was conducted in 26 hospitals in 9 countries. This was a non-inferiority trial, and the primary endpoint was all-cause mortality at 30 days after randomization.14
The MERINO trial was terminated early after enrolling 391 patients (PTZ, n= 196 and meropenem, n=195). The 30 days all-cause mortality in the PTZ group was significantly higher compared to the meropenem group (12.3% vs 3.7%) [risk difference, 8.6% (1-sided 97.5% CI, −∞ to 14.5%); P = 0.90 for non-inferiority]14. The authors concluded the PTZ was inferior to meropenem in the treatment of ESBL producing E. coli or Klebsiella spp. resistant to ceftriaxone but susceptible to PTZ.14
PTZ and Vancomycin-Induced AKI
Acute kidney injury (AKI) incidence in critically ill patients ranges from 22% to 57%.15,16 AKI presents several challenges as well as higher mortality in critically ill patients.15,16 As mentioned earlier, vancomycin and PTZ are the first and second most commonly used antibiotics in critically ill patients.7 If combining PTZ and vancomycin creates an additional risk for developing AKI in critically ill patients, then we may need to re-evaluate our initial empiric antibiotic strategies in critically ill patients.
A meta-analysis was conducted by Luther et al. of 15 studies and 17 abstracts that evaluated the risk of AKI with PTZ plus vancomycin compared to other antibiotic combinations (vancomycin monotherapy, vancomycin plus cefepime or carbapenem, or PTZ monotherapy).17 This meta-analysis included 24,799 adult patients. The PTZ plus vancomycin group had a 22.2% incidence of AKI, which was significantly higher than the incidence in all the other combinations (12.9%) (P<0.0001). It is important to note that only 968 patients of 24,799 patients (3.9%) were critically ill.17
Buckley et al. conducted a retrospective cohort study that included 333 critically ill patients. The authors compared the incidence of AKI with PTZ plus vancomycin compared to cefepime plus vancomycin.18 The incidence of AKI was not different between the two groups; 19.5% in the PTZ plus vancomycin group compared to 17.3% in cefepime plus vancomycin group (P=0.61). However, there was a significant increase in need of renal replacement therapy in the PTZ plus vancomycin group (10%) compared to cefepime plus vancomycin group (3.8%) (P=0.04).18
A single-center, retrospective cohort study compared the incidence of AKI in PTZ plus vancomycin to cefepime plus vancomycin and meropenem plus vancomycin.19 This study included 2,492 critically ill patients. The incidence of AKI was 39.3% for PTZ plus vancomycin, 24.2% for cefepime plus vancomycin, and 23.5% for meropenem plus vancomycin (P<0.0001 for all 3 comparisons).19 The authors conducted a multivariate analysis which showed the PTZ plus vancomycin combination was an independent predictor of AKI (OR 2.161; 95% CI, 1.62-2.833).19
On the other hand, a single-center retrospective cohort study compared the incidence of AKI in PTZ plus vancomycin to cefepime plus vancomycin and meropenem plus vancomycin in critically ill patients receiving short courses of the combination antibiotics (24-72 hours).20 This study included 3,299 critically ill patients. The authors did not observe a difference in the incidence of AKI between the groups.20 Adjusted OR for PTZ plus vancomycin compared to cefepime plus vancomycin was 1.11 (95% CI, 0.85 - 1.45) and adjusted OR for PTZ plus vancomycin compared meropenem plus vancomycin was 1.04 (95% CI, 0.71 - 1.42).20 This study showed a lower risk of AKI if PTZ was used for less than 3 days. However, the current recommendation is to treat bacteremia for 7-14 days, which can put patients at risk if clinicians were reluctant to de-escalate early.
Where we go from here?
It is time to rethink the practice of blanket coverage of every critically ill patient with PTZ. We should individualize empiric antimicrobial therapy based on patient history, site of infection, and MDR pathogens risk factors.
The use of PTZ should be reserved for situations where anaerobic coverage is needed, such as diabetic foot infections or complicated intra-abdominal infection. Historically, anaerobic coverage was considered a cornerstone in the treatment of aspiration pneumonia. However, studies have shown that the pathogenesis of aspiration pneumonia has shifted from anaerobic to aerobic pathogens.21 Anaerobic coverage may be still needed in patients with poor dental health21. These findings raise the question, do we still need to use PTZ in pneumonia?
Based on the current evidence, it seems that there is an association between PTZ plus vancomycin and the risk of AKI. The data in critically ill patients is still conflicting — a prospective study in critically ill patients is needed to determine the causality.
PTZ is an excellent antibiotic and still offer excellent coverage in situations when broad gram-negative and anaerobic coverage is needed, but other alternatives can be used when it comes to pneumonia, SSTIs, or blood-stream infections.
Alternatives to PTZ include ceftriaxone, cefotaxime, or ampicillin/sulbactam for severe community acquired pneumonia and ceftazidime, or cefepime for HAP/VAP.4
As the incidence and prevalence of multi-drug resistance are increasing worldwide, we as critical care clinicians need to take steps to ensure the appropriate use of all antimicrobials, not just PTZ. The following are suggested measures to improve appropriate antimicrobial use:
Submit for CE
UMKC’s SSHP chapter had a productive spring semester! In January, we kicked off the semester with a new event. KSHP and KU School of Pharmacy invited us to join their Pharmacy Forecast Workshop. Students learned about emerging healthcare trends and future opportunities of pharmacy practice. Time was also spent working in groups to discuss current practice problems and solutions.
All three campuses stayed busy hosting events. In February, our Columbia campus once again teamed up with MMSHP and the Ronald McDonald House. They helped prepare meals for patients and families receiving care at the Women’s and Children's Hospital, and collected pull tabs to raise money for the house. Our Columbia and Springfield campuses each held a “Vial of Life” event, in which patients were assisted in filling out a list of their medications for handy access during an emergency. Columbia members did this at the VA Hospital, while Springfield members did this at a Fearless Aging Expo. It was a great time serving the local community through these events.
We held our monthly general meetings throughout the semester with visiting speakers to share their experiences working as health-system pharmacists. One noteworthy speaker we had was Diana L. Dabdub, the Director of the Pharmacy Student Forum at ASHP. She presented on Practice Advancement Initiative (PAI) and empowered our students to play a role in improving patient outcomes in acute and ambulatory care settings. As pharmacy students, we want to help our current and future patients achieve optimal health outcomes by ensuring medication use is safe and effective. One way we can do this is by learning about practice advancement opportunities now. For many of the attendees, this was their first time hearing of PAI and enjoyed learning how they could make a difference.
During the week of final exams, our SSHP chapter educated our students on well-being and resilience through the power of social media. SSHP posted in each class’s Facebook page about ASHP’s initiative to promote resilience in pharmacy students. Education topics included positive thinking, setting goals, creatively solving problems, and much more.
This summer, the executive team is busy gearing up for our main events that happen in the fall semester. Residency program directors should be on the lookout for their invitation to attend Residency Roundtable, which will take place at each UMKC campus: Kansas City, Columbia, and Springfield. Our clinical skills competition and membership drive will also be taking place this coming fall.
We are thankful for your involvement with SSHP and wish you the best! All three campuses are excited to start the new school year in August and are ready to see our chapter grow, serve, and learn.
Throughout the Spring Semester of the 2018-2019 academic year, the STLCOP chapter of SSHP focused on expanding its core mission with regards to providing community outreach and health-system service activities, professional development, and networking opportunities for its student members.
As part of its health-system service initiative, STLCOP SSHP continued its annual fundraising project called Pants with a Purpose. This fundraising event was publicized to STLCOP students and faculty, in which for every pair of sweatpants purchased, another pair would be donated to the St. Patrick’s Center for the Homeless. Other essential items and basic necessities were also donated to help improve the health of the less fortunate in the St. Louis community. Through this community outreach event, the chapter was able to raise and donate about $500 in clothing and household needs. Blankets for Cancer Patients was another health-system service and volunteer opportunity for students to make blankets for oncology patients at Siteman Cancer Center. Cancer Care Packages was another well-received, recurring event held towards the end of the semester where students were able to put together care packages and hand-deliver them to patients at Siteman Cancer Center. This provided students, who haven’t already done so already, with the opportunity to tour Siteman’s outpatient infusion center and learn about oncology pharmacy from the pharmacists who worked there.
As part of the Community Outreach Initiative, STLCOP SSHP held a series of vaccination clinics and training sessions for students who wanted to practice administering vaccines. These clinics were held across various Shop N’ Save and Walgreens pharmacies throughout the greater St. Louis area, and students were given the opportunity to promote the importance of yearly flu shots and timely vaccinations, such as the Shingrix vaccine for Shingles. Students were thus able to implement what they had learned regarding how to administer vaccinations in a real-life setting, where they were able to interact with patients while doing so and impart their knowledge to the community.
As part of the chapter’s spring semester initiatives for professional development, STLCOP SSHP held a Residency Preparation Program which included a CV Review event and Mock Interview. Students were able to have their CV’s and resumes reviewed and critiqued by various faculty members. STLCOP SSHP believes that it is important for students to develop their CV’s and resumes early in their professional years, as it can only benefit them as they may apply to various jobs and internship opportunities throughout their years in pharmacy school. During the Mock Interview Practice Sessions, students were able to partake in a residency, fellowship, or job interview simulation conducted by various pharmacy practice faculty. This gave students the opportunity to sharpen their interviewing skills and know what kind of questions to expect in a potential residency interview. Faculty provided feedback to students and also answered questions regarding their potential career path into different pharmacy specialties.
STLCOP SSHP also aimed to continue providing students with ample networking opportunities with practicing pharmacists. During the Practice Advancement Initiative (PAI) Week in February, the chapter expanded its yearly series of health-system panels by introducing a Networking Roundtable with PGY1/PGY2 Residents. Students were able to network and connect with residents from different programs and hospitals throughout the St. Louis area. This provided students with a unique opportunity to learn about the daily roles and responsibilities of a pharmacy resident, how to best prepare for the residency application process, and what residency programs would typically seek in and expect from their candidates. The chapter also arranged a Clinical Roundtable networking event, where students were able to learn about the daily duties and roles of a clinical pharmacist, the impact that clinical pharmacists make in patient-centered care, and the different pharmacy specialties that students can pursue in pharmacy. The chapter also hosted several panels, seminars, and Lunch N’ Learns, where students were able to hear about interesting and important topics in healthcare such as hypertension management, skin cancer, and home infusion pharmacy. Lastly, the STLCOP SSHP chapter reintroduced our Aseptic Technique Lab for the first time in three years, during which students were given the opportunity to learn how to compound sterile preparations and IV admixtures.
Wow, I can’t believe we just wrapped up another very busy at the UMKC School of Pharmacy, and yet the new academic year is almost upon us! Thank you for the opportunity to provide an update, and thank you to all MSHP members who have had a huge impact on the education of UMKC student pharmacists! Although it would be impossible to describe everything going on, I would like provide a brief update on recent happenings at the school.
APhA-ASP at UMKC Does it Again! Well, there they are again in the limelight! The UMKC chapter of the American Pharmacists Association-Academy of Student Pharmacists (APhA-ASP) once again received a runner-up award in chapter achievement for their division placing them among the top 7 most accomplished chapters in the country! This continues a long running streak of national placement going back 9 years, including the fact that last year our APhA-ASP chapter was recognized as the top chapter in the country. This year, our chapter was also recognized as #1 in the nation for Generation Rx, #2 in the nation for Operation Diabetes, and #3 in the nation for Over-the-Counter Medicine Safety. Awesome! And, drum roll please, Jordyn Williams won FIRST place in the APhA-ASP National Patient Counseling Competition—a UMKC first!
Other National Student Awards. Our students received many other national awards. The National Community Pharmacists Association announced the top three proposals submitted to their Good Neighbor Pharmacy NCPA Pruitt-Schutte Student Business Plan Competition. Congratulations to Aaron Hunsaker, Kayla Shaw, Kayla Copeland, and Dylan Detlor and their faculty mentor Dr. Heather Lyons-Burney for having their business plan proposal chosen as a Top Three proposal out of 193 student entries! Other national award winners included: Kaitlyn Riggs selected for the 2018 Paul Ambrose Scholars Program of the Association for Prevention Teaching and Research; Emily Oliver selected for an APhA Student Leadership Award; and Jackie Bradley selected as 1 of only 10 nation-wide who won the United States Public Health Service Excellence in Public Health Pharmacy Award.
Other Important Measures of Student Success. We love the national attention our students bring to UMKC through all of their many accomplishments and awards. However, truth be known, there are a few major metrics which trump the awards. As for graduation, 92.9 % of the students who entered our program in 2015 graduated on time in 2019. While we do not yet have NAPLEX pass rates from them, we do know that for 2018 graduates—94.4 % of whom graduated on time—93.3 % passed the NAPLEX on first sitting and 97.8 % passed by the end of 2018. Further, their MPJE pass rate was also 93.3 % compared to 83.7 % national average. And again, while we do not have full placement data yet for our 2019 graduates, we do know that more than 68% of our 2019 graduates who applied for PGY1 residency training matched. Of them, 55 students will conduct their residency training at Missouri institutions including Kansas City’s Truman Medical Center, Saint’s Luke’s Hospital, Children’s Mercy Hospital, Research Medical Center, and North Kansas Hospital as well as University Hospital in Columbia and Cox Medical Center and Mercy Hospital in Springfield. Many also placed at other highly competitive national programs including Duke University, the Medical University of South Carolina, University of Illinois-Chicago, Wake Forest and others across the country.
Outstanding Faculty Accomplishments in 2018-2019. The many successes of our students no doubt reflect the outstanding guidance and instruction they receive from our wonderful and accomplished faculty. In our Division of Pharmacology and Pharmaceutical Sciences, Dr. Kun Cheng received notice of award from National Cancer Institute that his grant to develop targeted delivery platform for checkpoint inhibitors, will be funded for the next 5 years at well over $1.75 M. This was on top of his National Institutes of Health (NIH) R01 grants in prostate cancer and liver fibrosis. Dr. Bill Gutheil also received a new NIH grant to study vancomycin-resistant enterococci—wow, we need some new drugs for that for sure! Dr. Heather Lyons-Burney created and led a proposal from UMKC, the St. Louis College of Pharmacy, and the Missouri Pharmacy Association that was funded by the Cardinal Health Foundation to provide “train the trainer” best practices for education on appropriate opioid prescribing. In addition to all that, we have successful board certifications of faculty to report including Drs. Brandi Bowers, Kendall Guthrie, Andy Smith, Eric Wombwell, and Diana Tamer. Further, I am most happy to report that Dr. Sarah Oprinovich in partnership with Balls Foods led the successful site visit for reaccreditation our ASHP accredited community pharmacy residency program. Many have recognized the teaching excellence of our faculty including the state as Dr. Jerry Wycoff was recognized with the Governor’s Teaching Award, and Dr. Angela Brownfield was selected as the Missouri Pharmacy Association’s UMKC Faculty Member of the Year. And, our student pharmacists recognized Drs. Kylie Barnes, Simon Friedman, Tom Johnston, Pete Silverstein, Morgan Sperry, Amanda Stahnke, Karyn Turla, and Eric Wombwell as Teachers of the Year.
Lucky for us, there are many other accolades that our students, staff, and faculty achieved this year, far too many to list in this update. If you can make time to come by and see us, we’d be happy to tell you all about it. You are all welcome to visit the school anytime at our sites in Kansas City, Columbia, and/or Springfield. We also appreciate your assistance in identifying any students who might be interested in pursuing pharmacy careers. Just let us know, we love to talk to anyone about our great profession! Best wishes to everyone in MSHP!!
On May 11, St. Louis College of Pharmacy capped off the end of the 2018-19 academic year by celebrating its 151st Commencement. During this year’s ceremony, 253 students were awarded a Doctor of Pharmacy, and 166 students were awarded a Bachelor of Science. These talented and dedicated individuals represent the future of the pharmacy profession, and we were thrilled to recognize their achievements.
With Commencement now behind us, we are reflecting on an exciting year that was highlighted by growth, leadership and innovation. As the College continues to work toward its vision to be a globally prominent leader in pharmacy and health care education, the 2018-19 academic year saw the establishment of four new health-care focused bachelor’s degrees, which will be implemented this fall as standalone programs.
Tailored to the demands of the market and the needs of students, the following new programs are specifically designed to provide future students with options and the ability to explore their passions within the context of health care:
In addition to the new programs being offered, the College is renaming its existing undergraduate degrees and offering them as a Bachelor of Science in Pharmaceutical Sciences with a choice of emphasis in Health Sciences or Health Humanities. The new name is designed to better represent the coursework contained in the degree program. Meanwhile, the curriculum for our Doctor of Pharmacy (Pharm.D.) program will remain unchanged, and students will continue to have the opportunity to integrate a bachelor’s degree with a Pharm.D. or apply to the Pharm.D. program after completing their prerequisites.
Through strategic partnerships, we are also creating opportunities for students at the College to pursue graduate education:
This expansion of our academic offerings comes as the College continues to see extensive growth in its research initiatives. Under the direction of Thomas Burris, Ph.D., FAAAS, FAHA, alumni endowed professor of pharmacology and vice president for research, the College’s Center for Clinical Pharmacology is humming with activity funded by the National Institutes of Health, the Department of Defense and the National Institute of Drug Abuse.
In recent months, the center has flourished with the addition of seven new faculty and more than 25 postdoctoral research associates, graduate and undergraduate researchers and technical staff members now working in its labs. Burris and the center’s team of researchers are focused on using chemical biology approaches to examine the physiological roles of nuclear hormone receptors and developing drugs targeting them for the treatment of conditions including chronic pain, type 2 diabetes, heart disease, cancer and Alzheimer’s disease.
The center unites pharmacists, physicians and researchers who hold academic appointments at both the College and Washington University School of Medicine in St. Louis, and the many innovative research efforts currently underway continue to pave the way for the center to become a national research leader in pain management and personalized approaches to medication therapy.
We are also thrilled to note that the 2018-19 academic year was highlighted by a wide range of recognition for members of the College community.
This is truly an exciting time at St. Louis College of Pharmacy! I invite you to visit campus soon for a first-hand look at the many wonderful things underway as the College continues its work to prepare students for expert practice and leadership in pharmacy and health care education, interprofessional patient-centered care and collaborative research.
The Membership Committee is pleased to share some of the results from the 2019 MSHP Annual Survey. This year 52 members responded to the survey.
Reasons for Being Involved
Networking was again selected by respondents as the primary reason for involvement in MSHP.
Top three reasons for being involved in MSHP:
2. Professional Development
3. Affiliate chapter activities and Continuing Education
MSHP meetings and CE, advocacy, and leadership opportunities were also frequently ranked by responders as top three membership benefits.
Overall, responders felt that MSHP is doing a good job fulfilling most organization activities.
Most important MSHP activities per responders:
1. Advocating for me and the profession of pharmacy at the state level
2. Delivering high quality education
3. Promoting the health-system pharmacy to the general public
4. Communicating key health-system pharmacy issues to members
MSHP activities which the organization is best fulfilling:
1. Providing opportunities of organizational involvement
2. Producing a high quality newsletter
3. Providing leadership opportunities
4. Delivering high quality education
Top Priorities for Coming Year:
1. Legislative Issues
3. Membership Involvement
Top Areas for Improvement:
1. Offer more local/regional programming
2. Offer more social functions and networking opportunities
3. Increase communication and programming around legislative issues
The majority of members indicated that they feel they receive a good value for their membership dues.
We want to thank all the members that took the time to fill out the survey. These results will be used during the next strategic planning meeting to guide organization initiatives.
We are excited about all the changes that have been happening within MSHP over the past year and look forward to continuing to improve your membership experience!