By: Michelle Tulchinskaya, Elena Stroman, and Katherine Nguyen; PharmD. Candidates
Mentor: Anastasia L. Armbruster Pharm.D., FACC, BCPS, BCCP
Since 2017, new therapies for Heart Failure with Reduced Ejection Fraction (HFrEF) have emerged reducing both mortality and hospitalizations for heart failure in this population. In particular, two drug therapies have emerged: angiotensin receptor-neprilysin inhibitors (ARNIs), and sodium-glucose cotransporter-2 inhibitors (SGLT2s). Overall, ARNIs, SGLT2s, and other guideline directed medical therapy (GDMT) are underutilized. CHAMP-HF has exhibited the underutilization of these medications.1 Specifically sacubitril/valsartan (Entresto®), has been underutilized even after the 2016 ACC/AHA/HFSA Focused Update on HF included it as a Class I recommendation for patients with HFrEF.2 In outpatient settings, 86.1% of patients without contraindications did not receive sacubitril/valsartan. Patients with the following characteristics were less likely to receive treatment; older age, Hispanic ethnicity, chronic insufficiency, and higher EF (p ≤ 0.009). Patients with higher systolic blood pressure and a history of hypertension were associated with achieving a ≥50% target dose (all p ≤ 0.037).1
Traditionally, angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) have been first line therapies for patients with Stage C HFrEF. The 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment is the first document to prefer the usage of ARNIs for patients with Stage C HFrEF over ACE-Is/ARBs.2 Neprilysin, also known as neutral endopeptidase, is a zinc-dependent metalloprotease that inactivates several vasoactive peptides, such as natriuretic peptides, adrenomedullin, bradykinin, and substance P, each of which has an important role in the pathogenesis and progression of HF.2 As demonstrated in the PARADIGM-HF trial, sacubitril/valsartan was associated with reduced hospitalizations, morbidity, and mortality in these patients compared to enalapril.3 The composite of death from cardiovascular causes or hospitalization for heart failure occurred in 914 patients (21.8%) in the sacubitril/valsartan group and 1117 patients (26.5%) in the enalapril group (HR in LCZ696 group: 0.80; 95% CI 0.73 - 0.87; P<0.001).4 Due to this pivotal trial and following guideline recommendations, the preference is to start patients on an ARNI at the diagnosis of Stage C HFrEF, transition patients from an ACE-I or an ARB, or start patients that have not been given an ARNI, ACE-I, or ARB. Recent data from clinical studies, along with aggregate clinical experience, suggest that directly initiating an ARNI, rather than a pretreatment period ACE-I/ARBs, is a safe and effective strategy.2 In the PIONEER-HF trial, it was concluded that sacubitril/valsartan’s efficacy and safety was consistent across dose levels in hemodynamically stable patients with advanced decompensated heart failure. In the randomized, double-blind, active-controlled trial sacubitril/valsartan versus enalapril, there was no heterogeneity across dose levels in the effects of sacubitril/valsartan on the reduction of NT-proBNP, reduction of cardiovascular death, rehospitalization, or pre-specified adverse events.5
Although it is recommended to use an ARNI, ideal timing of initiation and rate of titration are frequently discussed. Many providers are concerned that patients will not be able to tolerate target dose due to adverse effects such as hyperkalemia, hypotension, cardiac failure, dizziness, renal impairment, angioedema, and cardiac failure. A randomized, multicenter, open-label study comparing two different treatment initiation regimens of sacubitril/valsartan, concluded that it was feasible for about half of the patients to achieve target dose within 10 weeks. In the TRANSITION trial, about half of the HF patients reached the recommended target dose in 10 weeks (relative RR 0.90; 95% CI 0.79 - 1.02), and over 86% were able to maintain any dose for at least 2 weeks leading to week 10 (relative RR 0.96; 95% CI 0.92 - 1.01).6 When obtaining full dose, it was noted that adverse effects of hyperkalemia, hypotension, cardiac failure, dizziness, renal impairment, angioedema, and cardiac failure were low. These adverse events were reasons for patients’ discontinuation of sacubitril/valsartan as well.6 It was found that a better tolerability profile was obtained when the uptitration was done gradually and that patient’s tolerability was higher when baseline adverse effects and labs of the patients were taken into account. Another multicenter, randomized, open-label, parallel‐group study found that a more gradual/conservative uptitration can increase the chance of attaining the target dose of sacubitril/valsartan in patients transitioning from lower doses of ACEI/ARBs.7 Additionally, it was found that the majority of patients (>80%) with SBP of ≥100 mmHg achieved and maintained the target dose of sacubitril/valsartan if the treatment was titrated gradually.8 A gradual dose increase included patients on a low dose of 24 mg/26 mg twice per day, followed by a titration up to 97 mg/103 mg twice per day over a 3 or 6 week period.8 These findings suggest that low SBP should not prevent clinicians from considering the initiation of sacubitril/valsartan.
The mortality benefit of sacubitril/valsartan for HFrEF patients is notable as described in the PARADIGM-HF trial, but many patients struggle with access to the life-saving medication due to the high cost. Sacubitril/valsartan is covered by Medicare Part D, but the out-of-pocket cost can be more than $1,600 a year for patients. In a study conducted by DeJong, et al., more than 2,000 Medicare Part D plans were analyzed. While all plans fully covered sacubitril/valsartan, the results concluded that the average cost-sharing for a 30-day supply of an ARNI during the coverage period was $57, as opposed to a range of $2 - 5.00 for other heart failure medications such as ARBs, beta-blockers, and loop diuretics. The study estimated the subjects’ projected annual out-of-pocket costs to be $1,685, of which $1,632 of $1,685 (96.9%) would be attributable to the ARNI.9 Although Medicare Part D provides coverage for sacubitril/valsartan, patients would still be left with a considerable amount of out-of-pocket costs.
An additional analysis of the effectiveness and value of sacubitril/valsartan, conducted by Ollendorf, et al., looked at the lifetime cost-effectiveness of sacubitril/valsartan relative to ACE-I therapy. The analysis showed that the ACE-I had averages of 5.56 quality-adjusted life years (QALYs) and total costs of $123,578, while sacubitril/valsartan produced an additional 0.57 QALY and an additional $29,138 in costs.10 This shows that cost-effectiveness would exceed $100,000 per QALY gained if the benefits of sacubitril/valsartan over enalapril persist for 3.3 years.10 Another study by Gaziano, et al. examined the cost-effectiveness of sacubitril/valsartan in comparison to enalapril in HFrEF patients. The study estimated that there would be 220 fewer hospital admissions per 1000 patients with heart failure treated with sacubitril/valsartan vs. enalapril over 30 years and calculated sacubitril/valsartan’s incremental cost-effectiveness ratio of US $45,017 per QALY gained.11 These findings concluded that utilization of sacubitril/valsartan could result in more QALYs gained, prevention of premature death, as well as significant cost-savings through avoided hospitalizations.
There is sufficient evidence that exhibits sacubitril/valsartan’s benefit in HFrEF therapy, and updated guidelines now prefer the usage of ARNI. Sacubitril/valsartan has demonstrated a decrease in hospitalizations due to HFrEF in comparison to ACE-I/ARBs, in addition to cost-savings. Though there are concerns for tolerability of sacubitril/valsartan, it can potentially be avoided with a gradual uptitration to target dose. It would be beneficial to use sacubitril/valsartan over ACE-I/ARBs unless limited by contraindications, tolerability or cost limitations.
By: Ethan Cowell, PharmD Candidate 2022; University of Health Sciences and Pharmacy in St. Louis
Mentor: Joseph Van Tuyl, PharmD, BCCP; Assistant Professor of Pharmacy Practice/Pharmacy Clinical Specialist – Cardiology; University of Health Sciences and Pharmacy in St. Louis/St. Louis University Hospital
Background:Heart failure (HF) affected 6 million adults in the United States from 2015 to 2018 and costed approximately $30.7 billion dollars in 2012 alone.1 Economic estimates predict the total cost of HF will increase to $69.8 billion by 2030.1 Costs are primarily due to hospitalizations to treat HF and the comorbidities that commonly accompany this disease state. In 2014, the projected mean cost of primary HF hospitalizations was $11 billion (approximately $11,552 per hospitalization).2
HF can be exacerbated by many comorbidities including iron deficiency, which is defined as a serum ferritin <100 mcg/L or serum ferritin 100 to 300 mcg/L with a transferrin saturation (TSAT) <20%.3 Iron deficiency may be prevalent in up to 21% HF patients with anemia, and iron deficiency may be present regardless of the presence of anemia.3, 4 Iron deficiency leads to lower iron-sulfur cluster-based complex activity in the mitochondria of cardiomyocytes, thereby, impairing mitochondrial respiration, ATP production, and contractility.5 HF patients with comorbid iron deficiency, consequently, are at an increased risk for hospitalizations, decreased quality of life, and exercise intolerance.
Iron stores are regulated by serum hepcidin, an acute phase reactant. Inflammation from HF increases the production of hepcidin. Subsequently, hepcidin binds the ferroportin transporter, which is primarily responsible for gastrointestinal iron absorption and causes its lysosomal destruction. Consequently, HF patients have a decreased ability to absorb oral iron.3 This was observed in the IRONOUT HF trial, in which clinically insignificant improvements in serum iron and TSAT conferred by oral iron supplementation over a 16-week period demonstrated no significant improvement in the change in peak VO2 (difference, 21 mL/min; 95% CI, -34 to 76; P-value, 0.46) or 6-minute walk distance (difference, -13 m; 95% CI, -24 to 23; P-value, 0.19) compared to patients receiving placebo.6
To overcome the limitations of oral iron supplementation, many clinical trials have assessed the efficacy and safety of intravenous iron therapy to correct iron deficiency in HF. Intravenous iron supplementation may improve clinical outcomes in HF by increasing cardiac mitochondrial function.
Literature Review:Intravenous iron supplementation routinely improved functional capacity in randomized controlled trials of chronic HF patients. Study participants were generally characterized as New York Heart Association (NYHA) Class II-III with a left ventricular ejection fraction <45%, and all patients met criteria for iron deficiency (serum ferritin <100 mcg/L or 100-300 mcg/L with a TSAT <20%), regardless of concomitant anemia.7-10 In the FAIR-HF trial, intravenous ferric carboxymaltose improved self-reported patient global assessment and NYHA functional classification over 24 weeks of follow-up.7 Those results were replicated in the CONFIRM-HF trial in which intravenous ferric carboxymaltose improved patient’s 6-minute walk test (difference, 33 ± 11 meters; P=0.002), NYHA functional class, and Kansas City Cardiomyopathy Questionnaire scores when compared to placebo.8 Furthermore, the EFFECT-HF trial observed a significant improvement in peak VO2 with intravenous ferric carboxymaltose use.9 Thus, the 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure states that it might be reasonable to utilize intravenous iron supplementation in NYHA class II and III HF patients to improve quality of life and functional status (Class IIb; Level of Evidence B-R).10 Recommendations for intravenous iron supplementation in acute HF, however, are absent from the guidelines.
In a small prospective study, Reed et al. examined the safety and efficacy of intravenous sodium ferric gluconate 250 mg every 12 hours (total dose calculated by the Ganzoni formula, mean dose = 1,269 mg) in patients with NYHA class III-I HF and iron deficiency. The study showed that intravenous sodium ferric gluconate increased the hemoglobin by 1.2 g/dL (95% CI, 0.45-1.9; P=0.005), ferritin by 364.2 ng/ml (95% CI, 129.7-598.7; P=0.007), and TSAT by 10.5% (95% CI, 6.5-14.6%; P<0.001). Additionally, iron deficiency was no longer present in eight of the nine patients that followed up in the study.11 Kaminsky et al. further illustrated that patients with acute HF and anemia who received intravenous iron (mean dose = 1,057 mg) had greater improvement in hemoglobin in comparison to a no iron replacement (P=0.0001).12 The mean difference in hemoglobin from baseline for iron therapy was 0.74 g/dL on day 7 and 2.61 g/dL on day 28, whereas the control group only saw a mean difference of 0.01 g/dL and 0.23 g/dL on days 7 and 28, respectively.12 This study also found no statistical difference between iron therapy and the control group in respect to all-cause 30-day readmission rates (P=0.2787), but lack of statistical power precluded a definitive conclusion.12 In each study, intravenous iron was well-tolerated without significant adverse effects.11, 12
Recently, the AFFIRM-AHF trial assessed the effect of intravenous ferric carboxymaltose on the risk of total HF hospitalizations and cardiovascular death in patients stabilized after acute HF. Patients included were hospitalized with acute HF with a left ventricular ejection fraction <50% and iron deficiency (serum ferritin <100 mcg/L or 100-300 mcg/L with a TSAT <20%). Ferric carboxymaltose was administered as two repletion doses, up to 1,000 mg prior to discharge and six weeks later, based on patient weight and hemoglobin; subsequent doses were administered at 12 and 24 weeks if iron deficiency persisted upon follow-up. No significant difference in the composite endpoint of total HF hospitalizations and cardiovascular death between the intervention and placebo groups (RR, 0.79; 95% CI, 0.62-1.01; P=0.059). However, a pre-COVID-19 sensitivity analysis was performed and demonstrated a significant decrease in the composite primary outcome (RR, 0.75; 95% CI, 0.59-0.96; P=0.024). Ferric carboxymaltose also decreased in total hospitalizations (RR, 0.74; 95% CI, 0.58-0.94; P=0.013), days lost due to HF hospitalization and cardiovascular death (RR, 0.67; 95% CI, 0.47-0.97; P=0.035), and rate of first hospitalization due to HF or cardiovascular death (HR, 0.80; 95% CI, 0.66-0.98; P=0.030). Conversely, the trial did not find a significant difference in cardiovascular death between the two groups (HR, 0.96; 95% CI, 0.70-1.32; P=0.81).13 Therefore, the trial provided evidence of reduced HF hospitalizations with the use of ferric carboxymaltose in stabilized acute HF patients.
Recommendations:Intravenous iron supplementation is efficacious in patients with chronic or acute HF and iron deficiency by decreasing hospitalizations and improving exercise intolerance, NYHA functional classification, and quality of life. No major adverse events were observed by intravenous iron replacement. Patients admitted for acute HF should be screened for iron deficiency, and intravenous iron may be administered to decrease the risk of worsening HF symptoms and readmissions.
By: Veeraya White, PharmD Candidate 2022 – University of Health Sciences and Pharmacy in St. Louis
Mentor: Brooke E. Gengler, PharmD, BCCP; Pharmacy Clinical Specialist, Cardiology, SSM Health Saint Louis University Hospital
IntroductionCoronavirus disease 2019 (COVID-19) is a viral respiratory infection caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) which has become a significant threat worldwide. The infection triggers host defense systems resulting in activation of coagulation and thrombin generation, called thromboinflammation.1 As a result, some patients with COVID-19 encounter complications associated with cytokine overproduction, hypercoagulability, and thrombosis. Thromboinflammation may lead to a life-threatening condition, disseminated intravascular coagulopathy (DIC), a condition in which blood clots throughout the body use up available clotting factors thereby increasing the risk of bleeding.2,3 Anticoagulants (ACs), such as low molecular weight heparin (LMWH), and unfractionated heparin (UFH), are used to prevent thrombosis.2 This article will discuss the appropriate criteria for anticoagulant venous thromboembolism (VTE) prophylaxis in patients with COVID-19.
Literature ReviewEarly in the pandemic, clinicians identified that DIC was commonly associated with severe cases of COVID-19 that resulted in death.4 Upon closer examination, many of these patients experienced microvascular thrombosis or venous thromboembolism.5 As a result, several studies attempted to find an association between various biomarkers such as D-dimer and risk of thrombosis. One retrospective study from Wuhan, China found that patients with sepsis-induced coagulopathy scores (SIC) ≥4 or elevated D-dimers who were given prophylactic doses of LMWH had reduced mortality compared to those without.6
Larger, prospective, randomized controlled trials have explored whether prophylactic anticoagulation is enough to prevent thrombosis or if intermediate intensity, doses between prophylactic and therapeutic anticoagulation, should be used instead. The ACTION study evaluated extended duration therapeutic anticoagulation with rivaroxaban or enoxaparin during admission followed by rivaroxaban for 30 days after discharge in acutely ill COVID-19 patients. Compared to standard VTE prophylaxis, therapeutic anticoagulation increased the risk of bleeding without improving clinical outcomes.7 In critically ill patients, receipt of early therapeutic anticoagulation within two days of admission was not associated with reduced mortality.8 Preliminary data from the multi-platform randomized controlled trial (mpRCT) also indicate that therapeutic anticoagulation did not improve survival or days free from organ support compared to standard pharmacologic prophylaxis. This trial was stopped early due to futility.9 Based on currently available evidence, most COVID-19 patients admitted to the hospital should be initiated on standard VTE prophylaxis rather than an intensified regimen.
Application in Practice
Thrombosis prophylaxis in hospitalized COVID-19 patients
Recommended standard prophylaxis doses of anticoagulants (dose adjustments for renal function and obesity not included)10,12,13
Recommended intermediate doses of anticoagulants17
Duration of VTE prophylaxis after hospital discharge10
By: Joanna Callier, Pharm. D. Candidate Class of 2023; University of Health Sciences and Pharmacy in St. Louis
Mentor: Emily Reinke, Pharm. D., CVS Pharmacy
Chronic kidney disease (CKD) affects more than 14% of the general population with over 660,000 of those individuals having kidney failure, 468,000 having end-stage renal disease (ESRD) requiring dialysis, and 193,000 currently living with a functioning kidney transplant. The incidence of ESRD is steadily rising with approximately 21,000 new cases each year with limited treatment options and increasing morbidity and mortality. 1 Most landmark clinical trials evaluating the use of direct oral anticoagulants (DOACs)—including apixaban, rivaroxaban, edoxaban, and dabigatran—exclude patients on hemodialysis (HD) and those with severe CKD. The majority of the available clinical trials exclude CKD when the creatinine clearance is below 25 mL per minute or requiring dialysis, resulting in a lack of safety and efficacy data for DOAC use in patients with ESRD.2 Patients who suffer from CKD and ESRD are at an increased risk of experiencing a thromboembolic or major bleeding event.2 Renal impairment decreases platelet adhesion and aggregation increasing the risk of bleeding events in these individuals.3 Due to DOACs renal clearance, patients with CKD are more prone to serious complications such as anemia, cardiovascular disease, hypertension, fluid retention, and electrolyte disorders.4
The Food and Drug Administration (FDA) approved DOACs for several indications including non-valvular atrial fibrillation (NVAF) and the prevention and treatment of venous thromboembolism (VTE) after their development in 2010.5,6,7,8 Prior to DOACs FDA approval, warfarin, enoxaparin, heparin, and fondaparinux were the standard of care.9 Many clinical trials show apixaban to be the superior DOAC in reducing thromboembolic events and bleeding risks in the general population suggesting clinical trials including patients with CKD will manifest similar risk reduction in this patient population.9 In 2014, the FDA approved apixaban for anticoagulation in patients with ESRD, despite a lack of this patient population in the landmark ARISTOTLE trial.5 Studies like RENAL-AF and the retrospective study “Comparison of the Safety and Effectiveness of Apixaban versus Warfarin in Patients with Severe Renal Impairment” used the results of ARISTOTLE to support their trials with ESRD patients. The data on anticoagulation in ESRD is limited due to the insufficient number of clinical trials that include this patient population, making a true assessment of bleeding risks difficult.
ARISTOTLE:The ARISTOTLE trial is a randomized, double blind, controlled trial, which enrolled patients with NVAF to receive dose-adjusted warfarin or apixaban 5mg twice daily to evaluate these agents’ safety and efficacy in stroke prevention.10 The primary outcome was ischemic or hemorrhagic stroke or systemic embolism and the secondary outcome was with the rate of major bleeding events as defined by the International Society on Thrombosis and Hemostasis (ISTH). The study included some of the following criteria: patients with NVAF or atrial flutter, having a previous stroke, transient ischemic attack, or systemic embolism, and being older than 75 years.10 The primary outcome occurred at a rate of 1.27% per year in patients receiving apixaban and 1.6% in patients receiving warfarin (HR with apixaban, 0.79; 95% CI, 0.66 to 0.95; P< 0.001 for non-inferiority). Major bleeding events occurred at a rate of 2.13% per year for apixaban and 3.09% for warfarin (HR, 0.69; 95% CI, 0.60 to 0.80; P < 0.001).10 The results of ARISTOTLE show that apixaban was superior to warfarin in preventing stroke or systemic embolism while causing fewer major bleeding events. This results in lower mortality in the apixaban group than the warfarin group thus making it the more favorable treatment option. These results were applied to patients with ESRD, despite their exclusion from the trial.
RENAL-AF:The RENAL-AF trial enrolled patients with NVAF and ESRD requiring HD to receive apixaban 5mg twice daily or 2.5mg for adjusted renal dosing— having two of the following: ≥ 80 years of age, weight ≤ 60kg, or a serum creatine ≥1.5mg/dL—to dose-adjusted warfarin.11 This randomized, open-label, blinded end-point evaluation trial assessed the safety and efficacy of apixaban. Inclusion criteria included, NVAF, a CHA2DS2-VASc score ≥ 2, ESRD with HD ≥ 3 months, and require anticoagulation considered by the treating physician.11 The primary outcome assessed relevant non-major bleeding and major bleeding events as defined by the ISTH of apixaban versus warfarin. There were similar rates of clinically relevant non-major bleeding events between apixaban and warfarin (31.5% vs. 25.5%, P > 0.05).11 The findings of this trial show similar rates of bleeding and stroke between apixaban and warfarin in patients with ESRD on HD. A major limitation of this trial was that it ended early due to a lack of funding that led to the study not meeting power.
Comparison of the Safety and Effectiveness of Apixaban versus Warfarin in Patients with Severe Renal ImpairmentThis single-centered retrospective matched-cohort trial compared renally adjusted dosing of apixaban 2.5mg to dose-adjusted warfarin.12 Inclusion criteria included a CrCl < 25mL/min, a SCR > 2.5mg/dL, or were receiving peritoneal dialysis (PD) or HD. The primary outcome was major bleeding and the secondary outcomes included major bleeding events defined by the ISTH, relevant nonmajor bleeding events, and minor bleeding events in patients with ischemic stroke, NVAF, and VTE determined by a physician.12 This trial did not result in a statistical significance difference between the two drug groups in patients with ESRD in occurrence of bleeding, stroke, and VTE —resulted in a 33% power when 80% was needed.12 This trial however did find that less bleeding was present in the apixaban group, making this drug a potentially safer option in ESRD with close monitoring—this suggestion mirrors that of the ARISTOTLE trial.12 It is also important to note that bleeding occurred more often in this patient population than in the general population, most likely due to the increased risks of bleeding already present in ESRD mentioned previously.
Recommendations:Patients with ESRD are at higher risks of NVAF, stroke, and bleeding which can make this patient population more difficult to treat.13 The results of the analyzed trials show apixaban being superior to warfarin in treating NVAF and ESRD with higher risks of stroke.10,11,12 Although apixaban has shown to be a superior anticoagulation option for ESRD, the pharmacokinetics need further evaluation to ensure safety and efficacy in this patient population. The few studies that have focused on the pharmacokinetics of apixaban have results that suggest 2.5mg is appropriate whereas 5mg becomes supratherapeutic and may expose these patients to higher risks of bleeding.14 Apixaban is the only thoroughly studied DOAC in patients with ESRD, which suggests development of more clinical trials are necessary to determine the safety and efficacy of the remaining DOACs on market—edoxaban, rivaroxaban, and dabigatran. As patients are getting older and more people are requiring hemodialysis, it is important to have trials focused on ESRD to avoid gaps in care.
By: Emily Humphrey, PharmD; PGY1 Pharmacy ResidentMentor: Brandi Bowers, PharmD, BCACP; Clinical Assistant Professor, UMKC School of Pharmacy at MSU
Program Number: 2021-07-02Approved Dates: August 1, 2021 – February 1, 2022Approved Contact Hours: One Hour(s) (1) CE(s) per session
BackgroundObesity is a serious chronic disease affecting millions of people worldwide, and the prevalence of obesity continues to increase in the United States. This common condition has grown to epidemic proportions with 1.9 billion adults worldwide being overweight and 650 million obese in 2016.1 The global burden of obesity has continued to rise with over 4 million people dying each year as a result of being overweight or obese.1 Obesity and being overweight are major risk factors for several chronic disease such as cardiovascular disease, diabetes, musculoskeletal issues like osteoarthritis, and some cancers.1,2 Despite the growing risks and substantial burdens associated with obesity, less than five percent of eligible patients with obesity are treated with behavioral, pharmacological, or surgical interventions.3 With the advances over the last decade to improve the safety, efficacy, and availability of these modalities, now is the time to work towards reducing the obesity epidemic.4
Although anti-obesity agents can help patients achieve clinically significant weight loss, these medications are underutilized. This is may be due to providers not counseling on weight management, recommending lifestyle modifications alone, and the potential barriers to using these medications such as safety concerns, monitoring requirements, and cost.5,6 Understanding when it is appropriate to initiate weight loss medications, what medications are appropriate based on patient characteristics, and when medications should be discontinued is important to provide optimized patient care.
Patients that may benefit from weight loss should receive counseling on diet, exercise, and patient-specific goals for weight loss. The main focus for treatment of obesity should be to improve overall health of the patient by preventing or treating weight-related complications through weight loss versus focusing on weight loss alone.7 A weight loss of five to ten percent of baseline body weight within six months is a common initial weight loss goal, and weight loss of more than five percent is associated with numerous health benefits.8 In the Look AHEAD trial, patients with type II diabetes and body mass index (BMI) greater than 25 kg/m2 who participated in an intensive lifestyle intervention that aimed at and maintained a loss of at least seven percent body weight had more weight loss and improved glycemic control compared to standard of care.9 Patients achieving weight loss of at least ten percent within the first year had a reduced risk of fatal and nonfatal cardiovascular events at ten years.10 Setting SMART (Specific, Measurable, Achievable, Reasonable, and Time-bound) goals specifically related to behavior, dietary, and exercise changes will help patients achieve their overall weight loss goal of five percent.7,8 Weight loss can be extremely challenging for patients, especially if they are trying to manage implementing dietary, behavioral, and exercise changes all on their own. A multidisciplinary team approach involving physicians, pharmacists, registered dietitians, exercise specialists, and behavioral specialists can provide the patient with the support they need to achieve and maintain weight loss.11
TreatmentNonpharmacologicalSuccessful weight management requires realistic and sustainable treatment strategies. Lifestyle management should incorporate three key components: physical activity, meal plan, and behavior.7 The recommended amount of physical activity is 150 minutes of moderate intensity exercise per week which can decrease risk of all-cause mortality by 33% compared to no physical activity.12 Most Americans do not get enough physical activity, and reaching 150 minutes of moderate intensity activity starting out would be unrealistic goal for most patients. Exercise specialists as part of the multidisciplinary team can educate patients on practical ways to integrate physical activity into their day-to-day life.11 Patients should be encouraged to make small, manageable changes in physical activity that will be sustainable as they gradually increase activity as they are able to achieve at least 150 minutes of physical activity per week.
The goal of meal planning or dietary therapy is to reduce the total number of calories consumed. An average calorie deficit of 500 to 700 calories per day will result in approximately 0.5 kg/week weight loss initially.7 With the vast array of diet types and fad diets available, it can be difficult to choose a sustainable option. Conventional diets include balanced low-calorie diets, low-calorie versions of healthy diets (Mediterranean and Dietary Approaches to Stop Hypertension [DASH] diets), low-fat diets, low-carbohydrate and low glycemic index diets, high-protein diets, and very low-calorie diets. No single diet type fits all patients, and a variety of dietary interventions can help reduce calorie intake and promote weight loss. In a meta-analysis of 48 randomized clinical trials that compared different dietary programs with a comparator (no diet or competing dietary program), all diet programs showed significant weight loss (6 to 8 kg by six months) compared with no diet.13 This is why having a registered dietitian (RD) as part of the multidisciplinary team is so important. The RD can help patients determine which diet will best fit their needs and help the patient make simple, effective strategies to improve their diet and decrease overall caloric intake.11
PharmacologicalLifestyle interventions may not be enough for all patients. For patients who have already committed to lifestyle modifications but are still not achieving clinically meaningful weight loss of at least five percent at three to six months, it is appropriate to initiate anti-obesity medications in patients with BMI > 30 kg/m3 or BMI > 27 kg/m3 and a weight-related comorbidity such as diabetes, hypertension, hyperlipidemia, heart failure, cholelithiasis, osteoarthritis, gastroesophageal reflux disease, or obstructive sleep apnea.7 Medications currently approved for weight loss include phentermine and other sympathomimetics, orlistat, liraglutide, phentermine-topiramate, and bupropion-naltrexone. Sympathomimetic drugs should only be used for short-term management, while all other medications can be continued for chronic treatment. Lorcaserin (Belviq®) was previously recommended for long-term weight loss management but was removed from the market in early 2020 due to clinical trial data showing an increased occurrence of cancer.14
The sympathomimetic drugs (phentermine, diethylpropion, benzphetamine, and phendimetrazine) are only approved by the FDA for short-term use for up to 12 weeks in treatment of obesity due to their potential side effects and their high risk for abuse. These medications work for weight loss by stimulating the release of norepinephrine from the hypothalamus to reduce appetite. Although it is only approved for short-term use, phentermine is the most commonly prescribed weight loss medication in the US.15 Phentermine was originally approved in 1959 for short-term use for weight loss, and only one clinical trial from that period is available. This trial showed that phentermine given continuously or intermittently achieved greater weight loss than placebo (12.2 kg vs 4.8 kg).16 Though efficacious at reducing weight with short-term use, sympathomimetic drugs have several safety concerns with their use. Common side effects include increased heart rate and blood pressure, insomnia, and nervousness.7 Due to their effect on cardiovascular system, these medications are contraindicated in patients with cardiovascular disease (e.g., arrhythmias, heart failure, coronary artery disease, stroke, uncontrolled hypertension).7 Other contraindications include hyperthyroidism, glaucoma, history of drug abuse, and pregnancy.7
Orlistat is available via prescription (Xenical®) and at a lower dose over-the-counter (Alli®). Orlistat works by altering fat digestion through inhibition of pancreatic enzymes, thus inhibiting absorption of dietary fats by 30%. Due to its mechanism of action, orlistat should be taken during or up to one hour after each main meal containing fat and separated by at least two hours from multivitamins containing fat-soluble vitamins. When added to lifestyle intervention, orlistat helps patients achieve clinically significant weight loss of up to 10% of baseline body weight, maintain weight loss, and prevent weight regain. The XENDOS study was one of the longest trials evaluating the efficacy of orlistat. It showed significantly greater weight loss with orlistat versus lifestyle changes alone (5.8 kg vs 3 kg, p<0.001) and a lower cumulative incidence of diabetes with orlistat compared to lifestyle changes alone (6.2% vs 9%, p=0.0032) after four years.17 Contraindications associated with orlistat include pregnancy, chronic malabsorption syndrome, and cholestasis.18 Most common side effects associated with orlistat are gastrointestinal in nature, including cramps, flatus, fecal incontinence, anal leakage, oily spotting, and flatus with discharge.18 These side effects can be minimized by avoiding high-fat diets and following the recommended intake of no more than 30% total daily calories from fat.18
Liraglutide (Saxenda®) is a glucagon-like peptide-1 (GLP-1) agonist FDA-approved for weight loss and at a lower dose (max 1.8 mg daily) for treatment of diabetes under the brand name Victoza®. GLP-1 is an incretin hormone that increases glucose-dependent insulin secretion, decreases inappropriate glucagon secretion, slows gastric emptying, and decreases food intake. The efficacy of liraglutide for weight loss has been studied in patients with and without diabetes. In the SCALE trial, patients treated with 3 mg dose of liraglutide in combination with diet and exercise, achieved mean weight loss of 8.4 kg compared to 2.8 kg with diet and exercise alone (95% CI, -6 to -5.1; p<0.001).19 The SCALE-DM trial showed that overweight and obese participants with type II diabetes achieved greater weight loss with 3 mg dose of liraglutide compared to 1.8 mg dose and placebo over 56 weeks of treatment (6% vs 4.7% vs 2%, p<0.001).20 Contraindications associated with liraglutide include pregnancy, family or personal history of medullary thyroid cancer, or multiple endocrine neoplasia 2A or 2B. Acute pancreatitis has been observed with liraglutide in clinical trials and post-marketing reports; if pancreatitis is suspected, stop liraglutide and do not restart if pancreatitis is confirmed.21 Most common side effects include nausea, vomiting, diarrhea, and early satiety. Liraglutide is administered as a daily subcutaneous injection and should be titrated on a weekly basis or as tolerated from starting dose of 0.6 mg to a max of 3 mg for weight management.21
Phentermine-topiramate extended release (Qsymia®) combines the weight loss effects of a sympathomimetic agent with topiramate, which helps with weight loss by causing appetite suppression and enhancing satiety. The CONQUER study showed that the combination of phentermine-topiramate was efficacious in achieving clinically significant weight loss after 56 weeks at doses of phentermine/topiramate 15 mg/92 mg and 7.5 mg/46 mg compared to lifestyle interventions alone (-10.2 kg vs -8.1 kg vs -1.4 kg, p<0.0001).22 The SEQUEL study was an extension trial to CONQUER and showed sustained weight loss over 108 weeks with both doses of phentermine-topiramate compared to placebo, with the 15 mg/92 mg dose achieving greater weight loss than the 7.5 mg/46 mg dose (-10.5% vs -9.3% vs placebo -1.8%, p<0.0001).23 Additional side effects associated with topiramate in the combination product include cognitive dysfunction, dry mouth, paresthesia, and dysgeusia.24 Phentermine-topiramate is only available through a REMS program due to increased risk of fetal harm, specifically, risk of causing orofacial clefts in infants exposed to the combination drug during first trimester of pregnancy.25 While all anti-obesity medications are contraindicated in pregnancy, extra caution should be taken due to the risk for fetal harm with this medication. All women of reproductive potential should take a pregnancy test prior to starting the medication and monthly while on it and should use a reliable form of contraception.25
Bupropion-naltrexone extended release (Contrave®) is a combination product containing two drugs FDA-approved for other indications. The exact mechanism of the combination bupropion-naltrexone for weight loss is not fully understood but is thought to result from effect on areas of the brain involved in regulating food intake. The COR-I trial demonstrated efficacy of bupropion-naltrexone for weight loss management with average weight loss of 5% versus 1.3% with lifestyle intervention alone (p<0.0001).26 The most common side effects associated with bupropion-naltrexone are nausea, headache, and constipation. Other side effects include insomnia, vomiting, dizziness, and dry mouth.27 Bupropion-naltrexone carries a Black Box Warning due to the increased risk of suicidal thoughts and behavior in young adults (18 – 24 years old) associated with antidepressants such as bupropion.27 Bupropion-naltrexone is contraindicated in patients with uncontrolled hypertension, on chronic opioids/opiate agonists/partial agonists, prescribed other bupropion containing products, with a history of seizures or seizure disorders, with eating disorders, and with severe hepatic dysfunction.27 Bupropion-naltrexone should be used with caution in patients with cardiovascular disease as it can cause increase in blood pressure and heart rate and the cardiovascular safety outcomes associated with bupropion-naltrexone have not been established.27
All anti-obesity medications are efficacious in facilitating weight loss in combination with lifestyle interventions. Choice of anti-obesity drug should be based upon patient-specific comorbidities, presence of contraindications to medications, and side effects of the medications. Table 1 summarizes the information described above. Table 2 lists preferred weight loss medications based on clinical characteristics and comorbidities. Patients should be involved in the decision-making process. Thorough education and counseling about the medications available and safety concerns associated with each is necessary so patients can make an informed decision as to which agent is best for them.
The benefits of anti-obesity medications are typically lost when the treatment is discontinued. The efficacy and safety of the anti-obesity medications should be assessed at least monthly for the first three months of treatment and frequently reassessed thereafter. Efficacy and tolerability of anti-obesity medications can vary from patient to patient. In general, if a patient’s response to a weight-loss medication is < 5% weight loss after three months on a maximal dose of the medication or if the patient experiences significant adverse effects to the medication, the risk-to-benefit ratio should be reassessed and discontinuation of the medication should be considered.8 The exception to this rule is the lower dose of phentermine-topiramate. If a patient is on 7.5 mg/46 mg dose of phentermine-topiramate and has not lost at least 3% of their baseline body weight after 12 weeks, either discontinue or continue titration schedule to maximum dose of 15 mg/92 mg once daily.24 If using the maximum dose of 15 mg/92 mg daily of phentermine-topiramate and patient has not lost at least 5% after 12 weeks, then gradually discontinue therapy.24
SurgicalAnother option to manage obesity is bariatric surgery. Patients considered candidates for bariatric surgery include adults with a BMI >40 kg/m2, or a BMI of 35 to 39.9 kg/m2 with at least one serious comorbidity such as type 2 diabetes mellitus, poorly controlled hypertension, obstructive sleep apnea, osteoarthritis and nonalcoholic fatty liver disease.7,29 Bariatric surgery encompasses several surgical interventions and depending on the method used, patients can achieve weight loss ranging from 20 to 45 percent at 12 to 18 months post-procedure.29 Although not required, patients usually attempt lifestyle interventions with or without pharmacological agents before bariatric surgery is considered. It is important, however, that prior to bariatric surgery patients are be evaluated on their ability to incorporate nutritional and behavioral changes to ensure patients will be able to maintain weight management long-term after surgical intervention.29
A Look to the Future:With the growing need for aid in combating the obesity epidemic, drug manufacturers have been looking for new and safer options for managing weight loss. Since the publication of the 2016 AACE/ACE and 2013 AHA/ACC/TOS guidelines two prospective agents have surfaced for weight loss management: cellulose and citric acid hydrogeland semaglutide.
Cellulose and citric acid hydrogel, brand name Plenity®, is an FDA approved medical device for weight management in adults with a BMI of 25 to 40 kg/m2. It is currently only available through a telehealth consult on the drug manufacturer website, but it should be widely available by the end of 2021.30 Plenity® works by forming a three-dimensional matrix that occupies volume in the stomach and small intestine, creating a sensation of fullness and increased satiety.31 Unlike many of the other weight-loss agents available, Plenity® is very well tolerated with minimal side effects, making it an intriguing treatment option for most patients. Most common side effects associated with its use include gastrointestinal effects such as diarrhea, abdominal distention, flatulence, and abdominal pain. It has also shown to be an effective treatment option for a wider range of patients with weight loss of at least five percent in most patients with a BMI from 25 to 40 kg/m2 in conjunction with diet and exercise. This is unique to Plenity®, as the other anti-obesity agents currently on the market are only approved for weight loss for patients with a BMI of at least 27 kg/m2. The GLOW trial not only showed a greater average weight loss over lifestyle intervention alone, but it also demonstrated that patients treated with Plenity® have twice the odds of achieving at least 5% and 10% weight loss compared to lifestyle intervention alone.32 Plenity® is administered as three capsules twice a day with 16 ounces of water 20 minutes before lunch and dinner to work effectively.31
Semaglutide is another GLP-1 agonist, similar to liraglutide, that is currently FDA- approved for treatment of type II diabetes. While not currently FDA-approved for weight loss management, recent data has shown that it may be an effective treatment option weight loss in patients with and without diabetes. The STEP 1 trial showed average weight loss of 15.3 kg with semaglutide 2.4 mg given via subcutaneous injection once weekly compared to 2.6 kg with lifestyle interventions alone (estimated difference -12.7 kg; 95% CI, -13.7 to -11.7).33 In the STEP 4 trial, patients who continued on semaglutide 2.4 mg once weekly after a 20 week run-in period continued to sustain weight loss of 7.9% 48 weeks later whereas the patients who stopped semaglutide after 20 week run-in period saw an increase in weight of 6.9% at 48 weeks (difference -14.8% [95% CI, -16% to -13.5%]; p<0.001).34 Like liraglutide, the most common side effects associated with semaglutide are gastrointestinal in nature, it should be discontinued if pancreatitis is suspected, and it should not be used in patients that are pregnant or have a family or personal history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B.
With the prospects of cellulose and citric acid hydrogeland semagultide being widely available on the market soon for weight loss, managing obesity is becoming safer and more reliable. This area is continuing to grow with numerous clinical studies for weight loss management underway investigating new medications such as tirzepatide and setmelanotide to name a few.35
Conclusion:Obesity is a chronic condition affecting millions of people. With obesity being a major risk factor for several chronic disease states such as cardiovascular disease and type II diabetes, it is ever more important to start managing obesity appropriately. Anti-obesity medications can have a benefit in increasing weight loss when added to lifestyle modifications, but these medications are often underutilized. Pharmacist involvement within the multidisciplinary approach to weight loss can improve the appropriate use of anti-obesity medications in combination with lifestyle interventions to provide additional weight loss benefits. Understanding which medications can be used for weight loss management, when it is appropriate to start, efficacy of these medications, and the safety concerns associated with their use can help optimize utilization of these agents in combating the obesity epidemic.
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By: Nicole Diveley, PharmDCoxHealth | Springfield, MO
Program Number: 2021-07-01Approval Dates: August 1, 2021 – February 1, 2022Approved Contact Hours: 1 hour
IntroductionEvery forty seconds, someone within the United States has a myocardial infarction (MI), according to the Centers for Disease Control and Prevention (CDC).1 In the United States, 655,000 deaths are from heart disease annually.2 Of the 805,000 heart attacks that occur annually, 200,000 happen to individuals who have already had a heart attack. Due to the high incidence of recurrent MIs, preventing a second myocardial infarction from occurring is a priority.
Myocardial infarction is defined as cell death of myocardial tissue due to loss of blood flow leading to oxygen deprivation.3 Patients may experience a large amount of inflammation due to the damage and lack of oxygen. Patients experiencing an MI may feel chest pain or pressure; light-headedness; pain in the jaw, neck, or back; pain or discomfort in one or both arms; and shortness of breath.1 Women may experience non-traditional symptoms such as unexplained fatigue, nausea or vomiting.
Modifiable and non-modifiable risk factors exist for myocardial infarctions.4 Diseases such as hypertension, hyperlipidemia, diabetes mellitus and obesity can contribute to heart disease and increase the chance of having an MI. Other risk factors such as smoking, family history, and age can contribute to the chance of experiencing an MI.
Myocardial Infarction Treatment and Secondary PreventionThere are a multitude of diagnostic tests that can be run to verify if an MI has occurred. Some of these tests are more specific than others, and which ones are utilized will likely depend on the health system that the patient presents to. Typically, one of the first tests to be completed is a twelve-lead electrocardiogram, which measures the heart’s electrical system and can be used to verify if an MI has occurred and which type occurred.5 If patient is being transported by ambulance, this test is typically run while en route to the health care facility.
Blood tests can be utilized to assess the severity of an MI, as well as to assess how severe an infarction was.6 One enzyme that may be measured is creatine kinase – mb (CK-MB). Creatine kinase is an enzyme found within the heart and the muscles and can be released when there is damage. CK-MB is more specific to the heart muscle and increases when there is damage or inflammation of the cardiac tissue. CK-MB does not tend to stay elevated for more than 24 to 48 hours, so use is limited when trying to determine if an event occurred in a delayed presentation. C-reactive protein (CRP) is another marker of inflammation that may be measured.7 It is not specific to cardiac muscle, so it may be elevated due to inflammation elsewhere within the body. Troponin is a marker that is frequently measured in the setting of chest pain or suspected MI.6 Troponin is a protein released into the blood from contraction of the heart muscle and can be used to detect damage. Cardiac troponin has the highest sensitivity to the heart muscle and is also beneficial due to the prolonged elevation of the enzyme after an acute event.
Goals of therapy between the acute stage of an MI and the post-MI stage are vastly different. During the acute phase of an infarction, the goal of therapy is to prevent cell death by oxygen restoration.8 This can be done in a number of ways depending on the facility the patient presents to. Reperfusion therapy is recommended for any patient presenting with an MI who meets eligibility. Reperfusion therapy should be recommended when symptom onset began twelve hours or less from presentation. When available, percutaneous coronary intervention (PCI) therapy is the preferred method of reperfusion, particularly for ST-elevated MI (STEMI). The goal for symptom onset to treatment with PCI is 90 minutes or less for STEMI. When a patient arrives to a facility that is unable to perform PCI, the preferred method of reperfusion is fibrinolytic therapy if the patient is having a STEMI, with a door-to-fibrinolytic therapy (or door-to-needle) time of 30 minute.
Post reperfusion treatment, maintenance therapy is started. The goal of treatment in this phase is to prevent another acute coronary syndrome event and to prevent further damage to the cardiac muscle. While therapy is patient dependent, the majority of patients are started on a routine regimen including dual antiplatelet therapy, a statin, a beta-blocker, and an angiotensin-converting enzyme inhibitor (ACE-I). Low-dose aspirin should be started daily post-PCI and should be continued indefinitely. A P2Y12 inhibitor should be loaded and then continued post-hospitalization. The length of therapy for dual antiplatelet therapy is dependent upon whether or not a stent is placed, the type of stent the patient receives, and other independent patient factors. Beta-blocker therapy is recommended to start within 24 hours of an MI for patients without contraindications. An ACE-I is recommended to be started within 24 hours post-MI in patients with a reduced ejection fraction less than 40%. In patients unable to tolerate an ACE-I, an angiotensin receptor blocker (ARB) can be given instead. High-intensity statin therapy should also be started within 24 hours of patient presentation. The above regimens are vital in preventing another acute coronary syndrome event.
Review of colchicine indications and cardiovascular outcomes in trialsColchicine currently has FDA-approved indications for use in the prophylaxis and treatment of gout and in familial Mediterranean fever.9 Colchicine exhibits its action through binding to tubulins which block the assembly and polymerization of microtubules. Colchicine is currently being examined for its use in both the acute MI and as secondary prevention.10 It is being evaluated for benefit when used in acute coronary syndrome and as secondary prevention due its anti-inflammatory effects. A summary of the colchicine doses used in the trials investigating colchicine’s role in MI and coronary artery disease can be viewed in Figure 1.
The COLCOT trial was a randomized, double-blind trial which compared low-dose colchicine at a dose of 0.5 milligrams (mg) once daily versus placebo in patients within 30 days after myocardial infarction.10 The primary outcome was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke or urgent hospitalization for angina leading to coronary revascularization. This trial randomized 4745 patients which were followed for a median of 22.6 months. The primary outcome occurred in 5.5% of patients in the colchicine cohort and 7.1% in the placebo cohort. This finding had a HR of 0.77 (95% confidence interval 0.61 to 0.96) and a p-value of 0.02, which was statistically significant. When compared to placebo, patients that received low-dose colchicine also had a lower risk of ischemic cardiovascular events.
Another study, LoDoCo-MI, was conducted to investigate colchicine’s use post-MI.11 This was a randomized, double-blind, placebo controlled trial. This study evaluated 237 patients that were admitted with an acute MI. Patients were randomized to receive colchicine 0.5 mg once daily or placebo for thirty days. To be included, patients had to be enrolled within 7 days of the MI. The primary outcome was the amount of patients with a CRP level ≥2 mg/L after 30 days of treatment. This value was chosen as it had been determined that levels greater than two were associated with worse prognosis. This study found that after 30 days of treatment with low dose colchicine or placebo, 44% of patients treated with colchicine versus 50% of patients treated with placebo had a CRP level greater than 2 mg/L. This finding was not statistically significant with a p-value of 0.35. In conclusion, this study found that when treated with low dose colchicine for 30 days post-MI, there is a trend toward more participants meeting a CRP level less than 2 mg/L.
Colchicine has not only been studied post-MI but has also been studied in the acute phases of MI.12 A trial titled “Anti-inflammatory treatment with colchicine in acute myocardial infarction” was conducted to assess if colchicine had any effect during the acute phase of an MI. 151 patients who presented less than 12 hours from onset of pain with a STEMI were included. Patients were randomized to receive either colchicine (1.5 mg loading dose followed by 0.5 mg one hour later and then continued with 0.5 mg twice daily for 5 days) versus placebo for 5 days. In addition to colchicine or placebo, patients received standard of care treatment for the acute MI and standard medical therapy post-MI. The trial studied the area under the curve of CK-MB fraction concentration for the primary outcome. This trial found that in the colchicine cohort, the area under the curve for CK-MB was 3144 ng/h/mL with an interquartile range (IQR) of 1754-6940 ng/h/mL versus 6184 ng/h/mL with an IQR of 4456-6980 ng/h/mL. These findings were statistically significant with a p-value of <0.001. This study had positive findings for colchicine’s use in acute MI; however it was not adequately powered, so the findings should be further investigated with larger trials.
Additionally, colchicine’s use has been investigated for coronary artery disease. In the randomized, prospective, observer-blinded LoDoCo study, patients were randomized to receive either colchicine 0.5 mg once daily or placebo.13 532 patients underwent randomization. To be included, patients had to have a diagnosis of stable coronary artery disease, defined as no changes in the previous six months. The majority of the patients in this trial were also on aspirin and/or clopidogrel in addition to a statin medication. Participants in this trial were followed for a median of three years. The primary outcome of this trial was the composite incidence of acute coronary syndrome, cardiac arrest outside of a hospital, or non-cardioembolic ischemic stroke. This composite outcome occurred in 5.3% of the colchicine cohort and 16% of the placebo cohort. The hazard ratio for these findings was 0.33 with a confidence interval of 0.18 to 0.59 and a p-value of < 0.001, which was statistically significant. These findings suggest a number needed to treat of 11. This trial found that when compared with placebo, patients treated with low dose colchicine had a lower risk of cardiovascular events.
An additional trial, LoDoCo2, was conducted to compare colchicine 0.5 mg once daily versus placebo.14 This trial was a randomized, controlled, double-blind study in which 5522 patients with stable coronary artery disease were randomized to receive colchicine or placebo. Patients were followed for a median of 28.6 months. The primary outcome was a composite of death from cardiovascular causes, spontaneous myocardial infarction, ischemic stroke or ischemia-driven coronary revascularization. This study found that the composite endpoint occurred in 6.8% of participants in the colchicine cohort and 9.6% of participants in the placebo cohort. These findings have a hazard ratio of 0.69, with a 95% confidence interval of 0.57 to 0.83 and a p-value <0.001, which was a statistically significant finding. In conclusion, the LoDoCo2 study found that when colchicine at 0.5 mg once daily was taken, it resulted in a lower risk of cardiovascular events versus placebo.
The above studies also studied adverse effects within the population receiving colchicine. The largest reported side effects were gastrointestinal in nature.10,12,14 This aligns with the package insert labeling.9 For adverse effects, diarrhea, nausea, and abdominal pain had the highest incidence.
Figure 1. Summary of the colchicine trials and the doses used.
Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction (COLCOT)
0.5 mg once daily
Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease (LoDoCo)
Colchicine in Patients with Chronic Coronary Disease (LoDoCo2)
Low Dose Colchicine after Myocardial Infarction study: a pilot randomized placebo controlled trial of colchicine following acute myocardial infarction
Anti-Inflammatory Treatment with Colchicine in Acute Myocardial Infarction
1.5 mg loading dose then 0.5 mg one hour later, followed by 0.5 mg twice daily
Mechanism of Colchicine in MIIt has been proposed that colchicine is effective post-MI due to the anti-inflammatory properties it exhibits. It is thought that colchicine potentially exhibits actions on cellular adhesion molecules, inflammatory chemokines and the inflammasome.10 Colchicine’s use in coronary artery disease was largely investigated due to its anti-inflammatory properties.15 Colchicine exerts its anti-inflammatory properties in a slightly different way than typical anti-inflammatory agents. It is different from typical non-steroidal anti-inflammatory agents in the fact that it does not have any action on the arachidonic acid pathway but instead exhibits anti-inflammatory action through microtubule depolymerization. The anti-inflammatory properties are beneficial in acute coronary syndrome due to inflammation resulting from plaque formation and the dislodging of the plaque during the plaque rupture. Additionally, the cardiac tissue suffers damage when deprived from oxygen, which also leads to inflammation. While colchicine’s exact mechanism and role in therapy is being evaluated, the current studies have provided guidance for the continued research.
Due to the unique anti-inflammatory mechanism, colchicine has also been evaluated for additional cardiac disorders. When evaluated for benefit in pericarditis, some positive outcomes have been found. Colchicine was also evaluated for its use in atrial fibrillation, but the findings were not as compelling for potential benefit in this disease state.
ConclusionMIs and cardiac disease account for 655,000 deaths each year within the United States.2 While current therapy shows benefit, there is still room for improvement. Studies involving low-dose colchicine show promising results for use during the acute phase of an MI as well as post-MI.10,11,12,13,14 It is thought that colchicine’s benefits are due to its anti-inflammatory effects.15 While the potential new benefits of colchicine are exciting, there are some other factors that need to be considered prior to implementation into practice. A major consideration should be the available dosage forms in the United States. While colchicine is generic in the United States making it fairly cost-affordable in comparison to brand name drugs, it is only available in 0.6 mg tablets and a liquid formulation.9 The current literature with positive cardiac outcomes for colchicine use dosing in increments of 0.5 mg tablets, which is not currently available in the United States. Additionally, a majority of medical treatment is typically driven by insurance preferences. It is uncertain how insurance will cover the new use of colchicine for indications other than gout. Colchicine would be a useful treatment in patients especially high-risk for cardiac events post-MI as it has proven beneficial at preventing cardiac events when used at low doses. It does however have adverse effects that may be intolerable to patients and need to be a consideration when determining therapy.
By: Annie Stella, PharmD, BCPS; Centerpoint Medical Center, Independence, MO
In 2019, the Department of Health and Senior Services rules for hospitals were updated. Under CSR 30-20.100 Pharmacy Services and Medication Management now states that Missouri hospitals and emergency departments can send bulk medications home with patients upon discharge. Any multidose container that was used for or administered to the patient during their hospital stay may be sent with the patient at discharge when ordered by an authorized practitioner. This includes, but is not limited to, inhalers, ointments, creams, medications requiring the original container for dispensing, insulin pens, eye drops, ear drops, and infusions that are currently connected to the patient’s infusion device.
Written instructions for use shall be provided by a pharmacist, prescriber or a registered nurse at the time of discharge.
How to implement a send-home program
Many multidose medications are disposed of upon patient discharge. This provides no continued help to the patient and increases hospital cost for proper waste management of these medications. But what if we could provide transitional care for the patient and reduce hospital waste management costs at the same time? The key is ensuring proper labeling and instructions for use to the patient upon discharge that does not cause an unreasonable increase in workload for staff.
The Children’s Hospital and Clinics of Minnesota devised a system that utilizes the initial labeling when sent from the pharmacy as well as a generic supplemental label placed close to discharge. The supplemental label includes the hospital name and address as well as generic directions to “use as directed” with the prescriber’s name inserted and manufacturer of the product. The patient is then instructed to use the medication as directed on their discharge paperwork.
Patient Safety & Quality Healthcare (PSQH) published an article in 2009 in which Spectrum Health in Grand Rapids, Michigan, laid out the criteria for an implementation process for sending patients home with the multi-dose products they used while inpatient. If the agreed upon criteria were met, the patient would be provided with the multi-dose medication (inhaler, ophthalmic product, topical preparation or insulin product) upon discharge. The product had to be labeled according to federal labeling requirements. Hospital information would be printed on the label prior to dispensing for inpatient use, followed by a second label that would be applied to the clear bag containing the inhaler. Finally, the patient was offered counseling if they desired for the particular discharge medication.
The Big Picture
By: Sarah Cook, Pharm.D., BCPS; SSM Health St. Joseph’s Hospital – St. Charles
Although the 2020-2021 year brought many new challenges to MSHP due to the COVID-19 pandemic, the Board of Directors and committees still accomplished a lot! Read below to hear about all of the accomplishments from the last year.
Board of Directors and Strategic PlanThe Board of Directors got several things accomplished this year. We finalized restructuring our communications by electing our first secretary-elect. We began working to increase technician involvement in our organization by reinstituting and electing a technician liaison. We embraced the virtual environment the pandemic created and updated our strategic plan, hosted a midyear reception, held Spring Meeting, and completed a 2 year internal audit – all virtually. We also increased our advocacy by signing on to numerous initiatives with ASHP. We ended our year together by fully reviewing and updating the policy and procedures manual.
Despite approving the Strategic Plan in December 2020, MSHP accomplished many items on the Strategic Plan this year! This is directly attributed to the hard work of our committee chairs and members. The Strategic Plan has three priority areas:
The Public Policy Committee formed several task forces to advocate for pharmacist provider status in Missouri. A total of 17 MSHP members attended the MSHP Webinar during the 2021 Virtual Legislative Day. The Education and Newsletter Committees implemented a peer review process for Featured Clinical Topics published in the MSHP Newsletter. The Education Committee and New Practitioner Workgroup produced a number of educational webinars for pharmacists and technicians. The Membership Committee established a database to identify gaps in membership and invite new/lapsed members to join MSHP. The Newsletter and Website/Social Media Committees developed a public relations policy to ensure consistent processes and messaging is communicated through media outlets.
Education/ProgrammingThe Education and Programming Committees have continued to provide high-quality content for the MSHP membership through hosting webinars for pharmacists and technicians and a successful spring meeting earlier this year. So far, the Education committee has hosted two webinars and is currently working to host a third in August. The committee also partnered with the Newsletter committee to provide peer review for featured clinical articles as of January 2021, which has provided additional support for authors and increased quality of articles for MSHP members. The Programming committee collaborated with ICHP this year to host another successful virtual spring meeting that provided pharmacists and technicians a place to gather, network, and earn CE hours. Looking to the year ahead, the programming committee is excited to partner with KCHP to host the Spring 2022 (in person!) meeting.
MembershipThe Membership Committee has continued to partner with administrative services to assist in the recruitment of new MSHP members and the retention of current members throughout this past year. In order to maintain a current membership list for MSHP, the Membership Committee collaborated with affiliate chapter liaisons across the state of Missouri. Recruitment efforts have been a focus this year, with outreach to potential members for active, associate, retired, recent graduates, technician and student categories. Once recruited, each new member was sent a personalized welcome message from the committee. The Membership Committee assisted in the creation, distribution, and the analysis of results of the annual membership survey in Fall 2020. The committee has been working throughout the year on building a database to establish contacts in Missouri hospital pharmacy departments for the purpose of on-site promotion of membership activities. The committee has also been engaged in the evaluation of the diversity of MSHP’s membership, the discussion of avenues to generate revenue for MSHP, and the development of listservs for specialty practice areas to increase opportunities for collaboration. The Membership Committee was excited to experience growth with the addition of 5 new members over the past year and looks forward to strengthening further relations with its membership in the future!
NewsletterThe Newsletter Committee has continued to provide high-quality content for the MSHP membership through collaboration with students, residents, and pharmacists throughout Missouri. Throughout the issues this year, there were 22 featured clinical articles and 10 pharmacist continuing education articles, as well as various articles regarding public policy, MSHP updates, and other topics. The committee partnered with the Education Committee to start providing peer review for featured clinical articles in January 2021, which has been successful thus far and well received by authors. The committee has also been engaged in conversations regarding public relations, and looks forward to further streamlining requests for content included in the newsletter in the following year!
Public Policy2020-2021 was an extremely busy year for the Public Policy Committee, as we saw the culmination of many years of effort. Missouri is no longer the only state in the nation without a PDMP! Hospital based Tech Check Tech was approved by the Board of Pharmacy and rules are being written by DHSS. The Legislative Day was a resounding success, adding to various other advocacy efforts and presentations from throughout the year. In addition to all of the ‘normal’ work, the committee served the role of disseminating information during the pandemic…everything from regulatory waivers and PPE guidance to staffing discussions and COVID vaccination strategies. As always, the exceptional, engaged members of the committee proved the value of MSHP again and again.
Website/Social MediaThis year, the committee focused on website improvements and increasing social media presence. Significant updates to the website were completed and include a policy section, past presidents’ section, and updated CE program information. Website updates are ongoing and members may see more significant changes over the summer months! The committee also provided extensive social media posts as MSHP celebrated its 50th anniversary, highlighting MSHP’s “50 Favorite Things” and creating a video looking back on the history of the organization. The committee ended the term year with 165 Facebook posts related to member successes, health topics, policy updates, and MSHP events. This years’ social media efforts increased MSHP’s Facebook member engagement by 67%, and our newly-established Twitter and Instagram accounts have over 100 followers on each platform! Come join us today on Facebook (Missouri Society of Health System Pharmacists), Instagram (missouripharmacists) and Twitter (@Mopharmacists) as we continue to explore new, innovative ways to engage and inform our members.
By: Sarah Cook, PharmD, BCPS; Clinical Pharmacy Specialist, SSM Health St. Joseph Hospital – St. Charles
Opioid Use Disorder (OUD) is defined as “a problematic pattern of opioid use leading to problems and distress” according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition.1 Per the American Medical Association, approximately 3-19% of people who take an opioid pain medication will develop OUD, and 45% of those who use heroin first started abusing prescription opioids. Dependence to opioids can develop in as little as 4-8 weeks, and in patients who use opioids chronically, the absence of opioids can lead to withdrawal symptoms (generalized pain, nausea/vomiting, diarrhea, dilated pupils, restlessness, anxiety, insomnia, chills, cravings) which promotes further opioid use to avoid such discomfort.2 Due in part to the significance of withdrawal symptoms, many patients with OUD are unable to effectively cease using opioids without additional assistance. Medication-assisted treatment (MAT) for OUD is a strategy that can increase the likelihood of individuals abstaining from inappropriate opioid use, which can translate into reduced mortality, decreased rates of blood borne illnesses, and other clinical benefits.3
Since 1999, overdose deaths due to opioids in the United States have increased by approximately 6 times, with over 47,000 deaths due to opioid overdoses occurring in 2018.4 It is estimated that approximately 10.3 million people misused prescription opioids and 2 million people had an OUD in 2018.5 In response to this alarming trend, the U.S. Department of Health and Human Services declared the opioid crisis a public health emergency in 2017 and outlined 5 priorities, two of which were to “improve access to prevention, treatment, and recovery support services” and to “target the availability and distribution of overdose-reversing drugs.”6 One area that has been a focus of these efforts has been emergency departments, as they are often the location where people engage with the medical system following an overdose or when in opioid withdrawal. Although harm-reduction strategies such as distribution of naloxone, an opioid reversal agent, have become more common in emergency departments, initiation of MAT for OUD is far less common and has faced significant barriers and resistance to implementation.7
Medications for OUD
Medications that are FDA-approved for the treatment of OUD include methadone, naltrexone, and buprenorphine. Naltrexone is a competitive antagonist of the mu opioid receptor, which is the primary receptor responsible for the pain relieving, euphoric, and respiratory depression effects of opioids. By blocking this receptor, naltrexone prevents patients from experiencing the effects of opioids when they are used (unless they are used in especially high quantities), which may discourage use over time; it may also somewhat decrease cravings for opioids, although the exact mechanism for this is unknown. Naltrexone does not have restrictions on what providers are able to prescribe it, but patients must abstain from opioids for 7-10 day prior to initiating naltrexone therapy to avoid precipitating significant opioid withdrawal symptoms, which makes this medication generally inappropriate for initiation in the emergency department. Methadone, on the other hand, is a long-acting full agonist of the mu opioid receptor with a moderate binding affinity. It effectively reduces cravings, prevents withdrawal symptoms, and does not cause euphoric effects in patients tolerant to it. Unfortunately, however, methadone is quite dangerous if used to overdose, and due to a propensity for inappropriate use, it is only able to be dispensed for OUD in specially designated clinics in the United States. Since it only has moderate binding affinity, it does not effectively block the binding of more potent opioids, such as fentanyl. Due to some of the downfalls of naltrexone and methadone, buprenorphine is the ideal medication to use to initiate MAT for OUD in emergency departments.8
Buprenorphine differs from other prescription and non-prescription opioids as it is a partial agonist of the mu opioid receptor rather than a full agonist. As a partial agonist, buprenorphine does have pain-relieving effects, but unlike other opioids, it has a ceiling effect in relation to respiratory depression and euphoria which makes buprenorphine much safer to use. In addition, buprenorphine has much higher affinity for the mu opioid receptor than most other opioids, making it significantly more difficult to overdose with other opioids if buprenorphine is in a person’s system as it will be unable to be displaced from the receptor; however, this high affinity also causes buprenorphine to displace other opioids currently in a person’s system from the receptor which can at times precipitate withdrawal symptoms. Buprenorphine is indicated for use in both acute and chronic pain as well as OUD, and it comes in a variety of formulations, including oral and sublingual tablets, sublingual films, transdermal patches, long-acting injections, and subcutaneous implants. Some of these formulations also contain naloxone, the opioid reversal agent, which is only activated if the medication is not taken via the intended route – this is included to deter patients from abusing buprenorphine.9 In order to prescribe buprenorphine for OUD, providers have to obtain a Drug Addiction Treatment Act 2000 waiver (also known as an X-waiver) – although this is not nearly as restrictive as prescribing methadone, it historically required 8 hours of training for physicians (or 24 hours of training for mid-level providers) and currently restricts providers to having 30 active prescriptions for buprenorphine at a time during the first year, with increased capacity in subsequent years. However, a rule by the DEA also allows buprenorphine to be administered in an emergency department for up to three consecutive days by providers who do not have an X-waiver.10 (Recent changes to X-waiver requirements will be discussed later in this article.)
Buprenorphine in the Emergency Department
Although evidence existed for using buprenorphine maintenance therapy for OUD that showed benefits including decreased cravings, reduced all-cause mortality, decreased overdose mortality, improved quality-of-life, and reduced incidence of blood borne illnesses such as HIV and hepatitis C,11 evidence for its use in the emergency department setting did not start accumulating significantly until the past decade. One clinical trial showed that buprenorphine could be safely used in the emergency department for opioid withdrawal and resulted in a fewer emergency department visits when compared to symptomatic treatment alone.12 The ground-breaking study that drew significant attention to buprenorphine’s use in the emergency medicine setting was published by D’Onofrio and colleagues at Yale in 2015. In this study, patients with opioid dependence who reported non-medical use of prescription opioids or heroin use in the last 30 days were randomized into three treatment groups. The first group (“referral group”), which contained 104 patients, received a screening and referral to treatment using a handout containing information on addiction treatment providers arranged according to insurance coverage. The second group (“brief intervention group”), containing 111 patients, received a screening, a 10-15 minute manual-driven brief negotiation interview (BNI), and a coordinated referral including review of insurance eligibility and transportation assistance. The third group (“buprenorphine group”) contained 114 patients who received a screening, a BNI, treatment with buprenorphine if they exhibited moderate-to-severe opioid withdrawal, and a referral to the hospital’s primary care center with an appointment made within 72 hours. A sufficient supply of buprenorphine was prescribed to patients to continue their treatment until follow up. The primary outcome of this study was engagement in addiction treatment at 30 days, with 37% of patients in the referral group, 45% of patients in the brief intervention group, and 78% of patients in the buprenorphine group being engaged in treatment for OUD at 30 days, which was statistically significant. The buprenorphine group also showed a statistically significant reduction in the mean number of days of illicit opioid use per week. The results of this study, with almost double the amount of patients receiving buprenorphine maintained in treatment at 30 days, highlighted the potential for emergency-department initiated buprenorphine to play a key role in improving outcomes for patients struggling with OUD.13
Since the study by D’Onofrio and colleagues was published, a number of protocols for emergency-department initiated buprenorphine for OUD have been developed and shared. The Yale protocol, which is based off of the treatment strategy for the buprenorphine group in the study led by D’Onofrio, can be seen in Figure 1.14 The CA Bridge initiative which was inspired by the work being done at Yale15 has an extensive library of resources and protocols. This initiative has expanded upon the Yale protocol by expanding the treatment options for patients to include higher total doses of buprenorphine to be given in the emergency department, which has the potential to allow for a longer period of relief from opioid withdrawal symptoms and cravings when an X-waivered provider is not available to write a prescription to bridge patients to their outpatient follow-up appointment. See the Figure 2 for more details.16 Both protocols, as well as others that have been developed, involve screening for inappropriate opioid use as well as an assessment for opioid withdrawal, such as the Clinical Opioid Withdrawal Scale (COWS). If an individual does not yet have notable withdrawal symptoms, buprenorphine should not be administered at that time as it may cause precipitation of worse withdrawal symptoms by displacing other opioids that are bound to the mu opioid receptor. Additionally, naloxone distribution is included as a part of these protocols as a harm-reduction strategy in the event that an individual would continue to use illicit opioids after emergency department discharge. Finally, these protocols are primarily intended to be used by X-waivered providers who will be able to prescribe buprenorphine to be used as an outpatient to bridge patients until their follow-up appointment, but they are written in such a way that they could also be used by non-X-waivered providers in certain situations.14,16 By improving engagement in treatment and therefore increasing the likelihood of long-term abstinence from illicit opioid use, MAT with buprenorphine for OUD being initiated in emergency departments is a key strategy to combating the opioid crisis.
Figure 1 - Yale Protocol for Buprenorphine Initiation in the Emergency Department14
(Reprinted from https://medicine.yale.edu/edbup/treatment/.)
Figure 2 - CA Bridge Buprenorphine Hospital Quick-Start Algorithm16
(Reprinted from https://cabridge.org/tools/resources/.)
Addressing Challenges to Buprenorphine Use for OUD
Despite growing evidence on the benefits of initiating buprenorphine in the emergency department and development of evidence-based protocols that can be translated to a variety of different situations, there remains significant resistance to implementation. A large amount of resistance comes from stigma that is held by healthcare providers, the public, and patients themselves.7 Despite evidence to the contrary, some clinicians still do not see addiction as a medical disease but rather as a moral failing of the individual. Additionally, even those who do understand addiction to be a medical disease may view buprenorphine use as simply replacing one addiction for another. However, when used as directed for the indication of opioid use disorder, buprenorphine is being used as a medication with evidence to support its benefits and not as a substance of abuse.11 Also, as previously described, buprenorphine is generally safer than other opioids as it is a partial agonist with ceiling effects on respiratory depression and as it can block the binding of other opioids which may decrease risk of overdose if illicit opioids are used.10 Other concerns with implementing a program in the emergency department stem from clinicians’ lack of formalized training and knowledge regarding the diagnosis and treatment of OUD, false perceptions that starting MAT for OUD is outside the scope of practice for emergency medicine providers, and actual or perceived lack of resources to effectively implement a program.17 As MAT for OUD is most effective when used as maintenance therapy, prompt connection to treatment post-discharge is especially of concern.8 Fortunately, health system resources, grant funding, and government resources can help address some of these concerns.
A variety of strategies can be undertaken by health systems to assist with the implementation of buprenorphine programs in emergency departments. Key to any of these strategies, effective programs will have the support of hospital leadership to allocate both educational and administrative resources to the program.17 By increasing clinician’s understating of the science behind addiction and of the diagnosis and treatment of OUD through educational initiatives and advocacy, stigma may slowly be changed to compassion and motivation for some providers, leading to a culture change in the organization.3,7 A variety of educational resources are openly available online, including from Yale, CA Bridge, Project SHOUT: Supporting Hospital Opioid Use Treatment and others, but development of organization-specific materials regarding community treatment resources is also imperative to success.10 Additionally, clinicians who complete X-waiver training have been shown to be more comfortable in providing treatment with buprenorphine,17 so incentivizing providers to obtain this training and obtain an X-waiver can be an effective strategy to help increase participation and bolster the effectiveness of a buprenorphine program by expanding treatment options.18 Having local clinical experts provide guidance and share their expertise can also increase comfort levels with prescribing buprenorphine in the emergency department and can help drive changes in practice. Development of evidence-based, organization-specific protocols and order sets with clinical decision support also increase provider readiness and comfort in initiating buprenorphine.17 Finally, although access to continued treatment for opioid use disorder is of concern and often is reliant on many factors outside an individual health care organization, taking a multidisciplinary approach in implementing buprenorphine in the emergency department, including recovery coaches if possible, may help improve the likelihood of effectively connecting patients to continued treatment.8,18 As implementation of many of these strategies relies on buy-in and support from hospital leadership, presenting evidence on the research-based financial implications of potential cost savings may be beneficial in garnering support; studies show that multiple programs have been initiated with a cost of only approximately $100 per patient and that emergency department programs for treatment of OUD may save from $2000 to $6000 per patient year for patients covered by Medicaid.10 Funds obtained through both government and non-government grants can also alleviate the initial financial burden of program development and implementation for a health care organization.
Regulatory Issues and the Future of the X-waiver
Government resources and regulatory changes are also imperative to expansion of MAT programs for OUD in emergency departments. Since the opioid crisis was declared a public health emergency, a large amount of federal grant funding has been made available to states and health organizations to improve access to OUD treatment and services.6 Additionally, it has been shown that Medicaid expansion resulting from the Affordable Care Act of 2008 increased access to care and treatment utilization for OUD,7 with better access to MAT and a 6% decrease in the rate of opioid overdose deaths in expansion states compared to non-expansion states.19,20
The federal government is currently considering changing the regulatory requirement for providers to have an X-waiver to prescribe buprenorphine. In the meantime, as of April 2021, federal guidelines have been updated to remove the educational requirements for practitioners to obtain an X-waiver if they only desire to treat up to 30 patients at a time. Practitioners still must have a valid DEA registration to prescribe buprenorphine and need to file a Notice of Intent to obtain an X-waiver, but the barrier of completing training has been removed if clinicians do not intend to treat large numbers of patients.21 Further information regarding these changes and answers to frequently asked questions in regards to the new federal guidelines are available on the Substance Abuse and Mental Health Services Administration website.22
In the future, government agencies will need to continue to consider the implications and efficacy of requiring an X-waiver for prescription of buprenorphine for OUD. Replacing the X-waiver with broad requirements for the inclusion of education regarding diagnosis and treatment for substance use disorders in medical training programs and continuing education requirements for licensure to further improve access to MAT for OUD may be more effective in providing safe, widely-available OUD treatment.7,23 In France, where restrictions on buprenorphine prescribing were removed in 1995, increased use of buprenorphine for treatment of OUD was seen and opioid overdose deaths decreased by 79% within 3 years, which supports the concept of decreased government regulation of buprenorphine.24 Additionally, states and insurance payers that require coverage of buprenorphine to be contingent on concomitant counseling therapy should consider removing this requirement, as it limits access to care and the benefits of buprenorphine can be seen even in the absence of counseling; these restrictions especially impact rural areas where counseling services are less common.7,8
It is as important as ever for health systems and government agencies to dedicate resources to effectively implement buprenorphine programs in emergency departments, thereby improving outcomes for individuals struggling with OUD by increasing engagement in treatment. The emergency department is an ideal location to focus resources on as it is a common place for patients to present to following opioid overdose or in opioid withdrawal, and buprenorphine has been shown to be a safe and effective treatment option in this setting as well as for maintenance treatment of OUD. Although there are many barriers to implementation of buprenorphine programs in emergency departments, there are multiple evidence-based strategies to overcoming these barriers, and easing of training requirements to obtain an X-waiver will hopefully ease some of these barriers as well. Especially considering that provisional data from the CDC indicates that overdose deaths increased by over 25% from the previous year as of August 2020,21 there is an urgent need to expand this evidence-based treatment with buprenorphine in emergency departments nationwide.
By: James Unverferth, PharmD, BCPS; Pharmacist Clinical Specialist
SSM Health St. Mary’s Hospital – St. Louis
Feedback and how to effectively provide feedback is a topic becoming ever more relevant as the years go on mostly due to the “millennial” generation filling the roles of students and residents. Supporting the portrayal of millennials on TV and social media, studies have shown that millennials desire frequent coaching and feedback.3
Feedback is important because it helps learners to identify areas of weakness in which they can build on foundational skills and knowledge. If done correctly feedback should help students to establish goals and evaluate performance so that over time they become sufficient enough to rely only on themselves for evaluation and motivation. Additionally, preceptor feedback is a topic that is frequently cited on accreditation surveys for residency programs. Accreditation standards specify that this feedback needs to be specific and criteria-based. To lend guidance on how preceptors can help learners achieve this goal, ASHP has developed a 3 part competency-based approach (Figure 1) to evaluate resident performance of a program’s educational goals and objectives, resident self-assessment of their performance, and of the program itself.1 This approach, while effective, is mostly tailored towards residency programs and may not be completely applicable to all learning situations, so I have developed a 6-part approach to establish a process of providing quality feedback to any learner. I hope this process helps you realize the importance of providing constructive feedback and its relationship to growth of a learner.
Six-part Approach for Providing Effective Feedback
Part 1: Establishing Expectations
The first step in my 6-part approach is to establish expectations. This stage of the process of providing quality feedback can begin even before a learner starts on rotation. Knowing past experiences of learners and what stage they are in in their studies or career can help shape expectations for the preceptor. For example — expectations for a rotation are going to be different for a resident on their last rotation compared to an APPE student on their first rotation, compared to an IPPE student on their first ever experiential rotation. Regardless, it is important to involve the learner in the process of establishing expectations. Before a learner starts a rotation have them develop SMART goals for the rotation.
Having students develop SMART goals will help preceptors when it comes time to evaluate the learner’s performance throughout the rotation AND it is a good exercise to refresh learner’s memory on how to set proper goals to achieve therapeutic outcomes for patients.2 A SMART goal is specific, measurable, achievable, realistic, and timely. In addition to having learner’s create their own goals, studies have shown that physically writing out goals improves the likelihood of achieving those goals.2 Once you have the learners create goals, it is important to meet with them to discuss and hold them accountable for creating quality SMART goals. Once these are documented, criteria needed to meet these goals can be established between the preceptor and the learner so that expectations are clear for both parties at the beginning of the rotation.
Part 2: Creating Learning Opportunities and Part 3: Observing Learning Experiences
Parts 2 and 3 of the six-part approach go hand-in-hand. Creating and observing learning opportunities is important because well-developed and well-defined learning activities provide preceptors with the means for directly measuring performance and progress toward fulfilling the learner’s goals. Additionally, this is where learners can apply feedback received by the preceptor after previous experiences. If a student is struggling to grasp a concept or has difficulty applying feedback, this is the opportunity that preceptors can practice the four roles of preceptor to enhance learning; by instructing, modeling, coaching, and facilitating.1
Part 4: Providing and Documenting Formative Feedback
During or directly after a learning opportunity it is important to take the time to provide feedback to students. It has been shown that as more time-elapses between learning experience and feedback, the value of the feedback drops, so it is best to provide frequent feedback sessions, even if the sessions are short. On top of feedback immediately after a learning experience, a common practice utilized by preceptors and often appreciated by learners is to schedule a time at least once a week to discuss progress and what things are working or not working. During and after observation and feedback sessions it is beneficial for the preceptor to write down notes on feedback provided to the learner so that it can be followed-up on or relayed to the learner at a later time. This is important because it may help you be more specific and evidence-based, providing more weight to your recommendations to the learner. Additionally, it has been shown that time is one of the major barriers of providing effective feedback to learners so by taking notes in the moment this can help save time on the back end when reflecting on learner’s performance.4
As mentioned earlier, the goal of feedback is to help learners identify areas of weakness in which they can build on foundational skills and knowledge. It is not meant to degrade, belittle, or embarrass a learner. With this in mind, feedback should be goal-related and actionable. It should be diverse, which means that it should not only be correctional, but should also be affirmative, observational, or even just clarifications. Lastly feedback should focus on the process and not the person. For example – “James you are a quiet person, speak louder next time” instead you can say “It can be hard to hear over skype phone calls, you may want to speak loud and into the microphone next time”. These are just some of the many principles behind providing quality feedback. A quick Google search of “how to provide quality feedback” will result in over a billion hits with links to articles on qualities of effective feedback, but the qualities discussed here are those that appeared most often and found to be worth sharing.
Now that some of the qualities of effective feedback have been defined, it is time to discuss appropriate methods for delivering feedback to the learner. The first method is called the sandwich method or can also be referred to as pro/con/pro method. This method starts with the preceptor stating something the student did well, then something the student can improve on, and finishing with another thing the student did well. This method leaves the student feeling encouraged instead of down in the dumps. Each comment, both positive and negative, should meet criteria for feedback discussed on the previous paragraph in order to be a “good sandwich”. Some “sandwiches” to avoid include; a “plain sandwich” that offers feedback but lacks any areas for improvement, a “finger sandwich” that offers feedback that is not very informative and is light on comments overall, an “open-faced sandwich” that starts off with just negative comments, and finally a “low-carb sandwich” that does not identify any strengths at all.6
The next method is the SII method or Strengths, Improvements, Insights method. This method is good to use informally or if no specific criteria are available. As the name implies it involves highlighting strengths of the learner observed during the experience, ways in which performance can improve, and finally insight which involves reviewing relevant new discoveries/understandings that occurred during the experience. It can be sometimes hard to provide insights, so here it may be best to come up with some teaching points that student can use moving forward.6
The last method to discuss is the Pendleton Method. Anecdotally, this is the most common method used among preceptors as it encourages the student to self-reflect about each learning experience and evaluate their own performance before hearing from the preceptor. Here it is important to facilitate a discussion while remaining positive, making sure to focus again on the process and not the person. In the end the preceptor and learner should agree on an action plan to move forward with.6
Table 1: Feedback Methods6
o Highlight the positives in the performance
o Highlight the positives in the performance
o Focus on ways in which the performance could improve
o Focus on ways in which the performance could improve
o Identify new and significant discoveries/understandings that were gained concerning the performance area
o Identify new and significant discoveries/understandings that were gained concerning the performance area
• Student states what was good
• Evaluator states area of agreement and elaborates on good performance
• Student states what was poor and could have been improved
• Teacher states what could have been improved
• Action plan is agreed upon
After this formative feedback is provided, the expectation for the learner to apply it to future encounters. Again, if learners struggle to implement feedback this is where preceptors can implement the four roles described earlier to demonstrate ways in which the learner can improve. By repeating this process over and over throughout a rotation, the hope is that the learner’s performance will continuously grow so that they can reach the goals they set at the beginning of the rotation.
Part 5: Learner Self-Evaluation
At the end of the rotation when hopefully all the SMART goals set and, the learners should perform a self-evaluation. Here the learner should be encouraged to really spend the time reflecting on their performance to come up with things they have done well and things on which they can improve.
Part 6: Summative Evaluation with Preceptor
The summative evaluation should strengthen the message from the formative feedback sessions you have been providing throughout the rotation. Hopefully if you have been meeting with the student regularly to provide feedback after learning experience as was suggested earlier, this should be easy to come up with specific, evidence-based feedback. Several things to keep in mind while wrapping up rotation with the learner: go in with the right intentions. No matter how poorly the learner performed, this should not be a time to condemn/demoralize the student. It should also not be a time to make yourself seem powerful or superior. The purpose of the evaluation is to guide, support, and enhance the learner’s ability to become a successful pharmacist as well as self-evaluator and motivator. Additionally, a final evaluation should not be the first time a learner is hearing constructive feedback. It can be discouraging and unhelpful for a learner to hear that their performance was not up to par without ever getting the chance to remedy or improve. To that point, not every student on their final evaluation should be given an “A”. This can make it difficult to distinguish genuine superior performance and overall good work. So, don’t be afraid to be negative with your feedback as long as it is not the learner’s first time hearing the constructive feedback and it is delivered in a way with the learner’s best interest in mind.
To wrap up the six-part approach, here are some more tips that can be utilized to enhance both formative feedback and summative evaluation. Many of the things have been touched on before, but a few things not previously mentioned that should be kept in mind: environment – it is best to provide feedback in-person so that a discussion can be had between learner and preceptor. Ideally this should be private, especially if doing a summative evaluation. If on-the-fly feedback is necessary, make sure not to call out the learner but instead wait for a time to take the learner aside and provide instruction on how their performance can improve the next time. Another good tip: always focus on the future. Lastly, feedback is always better if it is individualized. It may be helpful to have a student send you strengths/weaknesses prior to rotation starting.5 This way you can relate feedback to those characteristics.