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.

Literature Evaluation:

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 Impairment
This 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.

References

1. Kidney Disease Statistics for the United States. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease. Accessed June 9, 2021.
2. Hylek EM. Apixaban for End-Stage Kidney Disease. Circulation. 2018;138(15):1534-1536.
3. Aursulesei V, Costache II. Anticoagulation in chronic kidney disease: from guidelines to clinical practice. Clin Cardiol. 2019;42(8):774-782.
4. Bello AK, Alrukhaimi M, Ashuntantang GE, et al. Complications of chronic kidney disease: current state, knowledge gaps, and strategy for action. Kidney International Supplements. 2017;7(2):122-129.
5. Bristol-myers Squibb Company. Eliquis (apixaban) [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202155s012lbl.pdf. July 2016. Accessed July 11, 2021.
6. Boehringer Ingelheim Pharmaceuticals. Pradaxa (dabigatran) [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022512s028lbl.pdf. November 2015. Accessed July 11, 2021.
7. Daiichi Sankyo. Savaysa (edoxaban) [package insert]. U.S. Food and Drug Administration. website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf. January 2015. Accessed July 11, 2021.
8. Janssen Pharmaceuticals. Xarelto (rivaroxaban) [package insert]. U.S. Food and Drug Administration. website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202439s017lbl.pdf. May 2016. Accessed July 11, 2021.
9. Chen A, Stecker E, A. Warden B. Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges. Journal of the American Heart Association. 2020;9(13).
10. Granger CB, McMurray JJV, Alexander JH, et al. Apixaban versus Warfarin in Atrial Fibrillation. New England Journal of Medicine. 2012;366(1):88-90.
11. Pokorney S, Kumbhani DJ. RENal hemodialysis patients ALlocated apixaban versus warfarin in Atrial Fibrillation. American College of Cardiology. https://www.acc.org/latest-in-cardiology/clinical-trials/2019/11/15/17/29/renal-af. Published November 17, 2019. Accessed June 9, 2021.
12. Stanton BE, Barasch NS, Tellor KB. Comparison of the Safety and Effectiveness of Apixaban versus Warfarin in Patients with Severe Renal Impairment. Pharmacotherapy. 2017;37(4):412-419. doi:10.1002/phar.1905
13. Van Zyl M, Abdullah HM, Noseworthy PA, Siontis KC. Stroke Prophylaxis in Patients with Atrial Fibrillation and End-Stage Renal Disease. J Clin Med. 2020;9(1):123. Published 2020 Jan 2.
14. Byon W, Garonzik S, Boyd RA, Frost CE. Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review. Clin Pharmacokinet. 2019;58(10):1265-1279. doi:10.1007/s40262-019-00775-z

By: Emily Humphrey, PharmD; PGY1 Pharmacy Resident
Mentor: Brandi Bowers, PharmD, BCACP; Clinical Assistant Professor, UMKC School of Pharmacy at MSU

Program Number: 2021-07-02
Approved Dates: August 1, 2021 – February 1, 2022
Approved Contact Hours: One Hour(s) (1) CE(s) per session

Learning Objectives

• Evaluate efficacy of various non-pharmacological interventions on reducing weight and improving overall health
• Identify when to initiate pharmacological treatment for obesity
• Compare benefits and risks associated with pharmacological agents available for weight loss management
• Determine appropriate weight loss agent based upon patient-specific characteristics
• Evaluate new agents coming to market for weight loss management

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Background
Obesity 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

Treatment
Nonpharmacological
Successful 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

Pharmacological
Lifestyle 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

Surgical
Another 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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References:

1. Obesity Overview. World Health Organization Website. Available from: https://www.who.int/health-topics/obesity#tab=tab_1. Published April 1, 2020. Accessed May 17, 2021.
2. Adult Obesity Causes & Consequences. Centers for Disease Control and Prevention Website. Available from: https://www.cdc.gov/obesity/adult/causes.html. Published March 22, 2021. Accessed May 17, 2021.
3. Dietz WH, Baur LA, Hall K, et al. Management of obesity: improvement of healthcare training and systems for prevention and care. Lancet. 2015;385(9986):2521-2533.
4. Gallagher C, Corl A, Dietz WH, et al. Weight can’t wait: a guide to discussing obesity and organizing treatment in the primary care setting. Obesity. 2021;29(5):821-824.
5. Del Re AC, Frayne SM, Harris AH. Antiobesity medication use across the veterans health administration: patient-level predictors of receipt. Obesity (Silver Spring). 2014;22(9):1968-1972.
6. Iwamoto S, Saxon D, Tsai A, et al. Effects of education and experience on primary care providers' perspectives of obesity treatments during a pragmatic trial. Obesity (Silver Spring). 2018;26(10):1532-1538.
7. Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical Care of patients with obesity. Endocr Pract, 2016;22:1-203.
8. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society [published correction appears in Circulation. 2014 Jun 24;129(25 Suppl 2):S139-40]. Circulation. 2014;129(25 Suppl 2):S102-S138.
9. Look AHEAD Research Group, Gregg EW, Jakicic JM, Blackburn G, et al. Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes Endocrinol. 2016;4(11):913-921.
10. Look AHEAD Research Group, Pi-Sunyer X, Blackburn G, et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes Care, 2007;30(6):1374–1383.
11. Blackburn GL, Greenberg I, McNamara A, et al. The multidisciplinary approach to weight loss: defining the roles of the necessary providers. Bariatric Times. 2008. Available from: https://bariatrictimes.com/the-multidisciplinary-approach-to-weight-loss-defining-the-roles-of-the-necessary-providers/ Accessed May 17, 2021.
12. Piercy KL, Troiano RP, Ballard RM, et al. The physical activity guidelines for Americans. JAMA. 2018;320(19):2020–2028.
13. Johnston BC, Kanters S, Bandayrel K, et al. Comparison of weight loss among named diet programs in overweight and obese adults: a meta-analysis. JAMA. 2014;312(9):923-933.
14. FDA requests the withdrawal of the weight-loss drug Belviq, Belviq XR (lorcaserin) from the market. Food and Drug Administration: Drug Safety Communication. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-withdrawal-weight-loss-drug-belviq-belviq-xr-lorcaserin-market. Published February 20, 2021. Accessed May 18, 2021.
15. Saxon DR, Iwamoto SJ, Mettenbrink CJ, et al. Antiobesity medication use in 2.2 million adults across eight large health care organizations: 2009-2015. Obesity (Silver Spring). 2019;27(12):1975-1981.
16. Munro JF, MacCuish AC, Wilson EM, et al. Comparison of continuous and intermittent anorectic therapy in obesity. BMJ. 1968;1(5588):352-354.
17. Torgerson JS, Hauptman J, Boldrin MN, et al. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004; 27(1):155-161.
18. Xenical (Orlistat) [prescribing information]. Montgomery, AL: H2-Pharma LLC and Greifswald, Germany: CHEPLAPHARMA Arzneimittel GmbH; August 2017.
19. Pi-Sunyer X, Astrup A, Fujioka K, et al & SCALE Obesity and Prediabetes NN8022-1839 Study Group. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11–22.
20. Davies MJ, Bergenstal R, Bode B, et al & NN8022-1922 Study Group. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA, 2015;314(7):687–699.
21. Saxenda (liraglutide injection 3 mg) [prescribing information]. Plainsboro, NJ: Novo Nordisk; December 2020.
22. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9774):1341-1352.
23. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95(2):297-308.
24. Qsymia (phentermine/topiramate) [prescribing information]. Campbell, CA: VIVUS Inc; October 2020.
25. Qsymia (phentermine and topiramate extended-release) Risk Evaluation and Mitigation Strategy (REMS). Campbell, CA: VIVUS Inc; Aug 2014. Available from: https://www.qsymiarems.com/. Accessed May 18, 2021.
26. Greenway FL, Fujioka K, Plodkowski RA, et al. & COR-I Study Group. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2010;376(9741):595–605.
27. Contrave (naltrexone HCl and bupropion HCl) [prescribing information]. San Diego, CA: Nalpropion Pharmaceuticals, Inc; March 2021.
28. American Diabetes Association. 8. Obesity Management for the Treatment of Type 2 Diabetes: Standards of Medical Care in Diabetes—2021. Diabetes Care. 2021;44(Supplement 1):S100-S110.
29. Mechanick JI, Apovian C, Brethauer S, et al. Clinical practice guidelines for the perioperative nutrition, metabolic, and nonsurgical support of patients undergoing bariatric procedures–2019 update: cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society for Metabolic & Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Endocr Pract. 2019;25:1-75.
30. Weight management without deprivation. FDA-cleared weight management therapy Plenity®|HCP [Updated 2020 Jul] Available from: https://www.myplenity.com/healthcare-professionals. Accessed May 17, 2021
31. Plenity (cellulose/citric acid) [prescribing information]. Boston, MA: Gelesis, Inc; April 2019.
32. Greenway FL, Aronne LJ, Raben A, et al. A randomized, double‐blind, placebo‐controlled study of Gelesis100: a novel nonsystemic oral hydrogel for weight loss. Obesity, 2019;27(2):205-216.
33. Wilding J, Batterham RL, Calanna S, & STEP 1 Study Group. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021.384(11): 989.
34. Rubino D, Abrahamsson N, Davies M, et al. & STEP 4 Investigators. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. 2021;325(14):1414-1425.
35. ClinicalTrials.gov [Internet] Bethesda (MD): U.S. National Library of Medicine. Available from: https://clinicaltrials.gov/. Accessed May 30, 2021.

By: Nicole Diveley, PharmD
CoxHealth | Springfield, MO  

Program Number: 2021-07-01
Approval Dates: August 1, 2021 – February 1, 2022
Approved Contact Hours: 1 hour

Learning Objectives

• Describe the epidemiology of myocardial infarction.
• Describe the mechanism of action of colchicine.
• Discuss approved indications for colchicine.
• Examine current literature for new indications for colchicine.
• Investigate a place in therapy for new indications.

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Introduction
Every 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 Prevention
There 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 trials
Colchicine 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.

Trial Name	Colchicine Dose
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)	0.5 mg once daily
Colchicine in Patients with Chronic Coronary Disease (LoDoCo2)	0.5 mg once daily
Low Dose Colchicine after Myocardial Infarction study: a pilot randomized placebo controlled trial of colchicine following acute myocardial infarction	0.5 mg once daily
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 MI
It 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.

Conclusion
MIs 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.

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References

1. Centers for Disease Control and Prevention. What is a heart attack? https://www.cdc.gov/heartdisease/risk_factors.htm. Jan 11, 2021. Accessed April 2, 2021.
2. Fryar CD, Chen T-C, Li X. Prevalence of uncontrolled risk factors for cardiovascular disease: United States, 1999–2010. NCHS data brief, no. 103. Hyattsville, MD: National Center for Health Statistics; 2012. Accessed April 2, 2021.
3. Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. J Am Coll Cardiol. 2007;50(22):2173-2195. doi:10.1016/j.jacc.2007.09.011
4. Centers for Disease Control and Prevention. Know your risk for heart disease. https://www.cdc.gov/heartdisease/risk_factors.htm. Dec 9, 2019. Accessed April 2, 2020.
5. American Heart Association. Electrocardiogram (ECG or EKG). https://www.heart.org/en/health-topics/heart-attack/diagnosing-a-heart-attack/electrocardiogram-ecg-or-ekg. Jul 31, 2015. Accessed May 7, 2021.
6. Haldeman-Englert C, Turley K, Foley M. Cardiac biomarkers (blood). University of Rochester Medical Center Health Encyclopedia. https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=cardiac_biomarkers. Access May 29, 2021.
7. Mayo Clinic Staff. C-rective protein test. Mayo Clinic. https://www.mayoclinic.org/tests-procedures/c-reactive-protein-test/about/pac-20385228. Nov 21, 2017. Accessed May 15, 2021.
8. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines [published correction appears in Circulation. 2013 Dec 24;128(25):e481]. Circulation. 2013;127(4):e362-e425. doi:10.1161/CIR.0b013e3182742cf6
9. Colchicine [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2012.
10. Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381(26):2497-2505. doi:10.1056/NEJMoa1912388
11. Deftereos S, Giannopoulos G, Angelidis C, et al. Anti-Inflammatory Treatment With Colchicine in Acute Myocardial Infarction: A Pilot Study. Circulation. 2015;132(15):1395-1403. doi:10.1161/CIRCULATIONAHA.115.017611
12. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61(4):404-410. doi:10.1016/j.jacc.2012.10.027
13. Hennessy T, Soh L, Bowman M, et al. The Low Dose Colchicine after Myocardial Infarction (LoDoCo-MI) study: A pilot randomized placebo controlled trial of colchicine following acute myocardial infarction. Am Heart J. 2019;215:62-69. doi:10.1016/j.ahj.2019.06.003
14. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020;383(19):1838-1847. doi:10.1056/NEJMoa2021372
15. Deftereos S, Giannopoulos G, Papoutsidakis N, et al. Colchicine and the heart: pushing the envelope. J Am Coll Cardiol. 2013;62(20):1817-1825. doi:10.1016/j.jacc.2013.08.726

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

We want to provide the best care for our patients while also supporting our own health-systems. This initiative, while seemingly simple, can balance the labeling and counseling services that are required by reducing hospital waste. At the end of the day, a send-home program will improve the care of Missouri patients. There is no better reward than that. Do you provide this service at your hospital? If so, share your ideas with us at mshp@qabs.com! 

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 Plan
The 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:

1. Improving patient care through education and practice advancement
2. Membership growth and enhancement
3. Organization and performance

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/Programming
The 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.

Membership
The 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! 

Newsletter
The 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 Policy
2020-2021 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 Media
This 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.

MSHP would like to thank all of the board members and committee chairs from 2020-2021 for all of their excellent work, and we look forward to everything MSHP will accomplish in the coming year!  If you would like to get more involved in MSHP through joining a committee, go to http://moshp.com/Committees.

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

Conclusion

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.

References

1. American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5 (5th ed.). American Psychiatric Publishing.
2. American Psychiatric Association. (2018, November). Opioid Use Disorder. American Psychiatric Association (APA). https://www.psychiatry.org/patients-families/addiction/opioid-use-disorder/opioid-use-disorder#:~:text=The%20Diagnostic%20and%20Statistical%20Manual,a%20longer%20period%20than%20intended.
3. Strugar-Fritsch, D. (2019, August). MAT for Opioid Use Disorder: Overcoming Objections. California Health Care Foundation. https://www.chcf.org/wp-content/uploads/2019/06/MATOpioidOvercomingObjections.pdf
4. Centers for Disease Control and Prevention. (2020, March 19). Data Overview | Drug Overdose | CDC Injury Center. Centers for Disease Control and Prevention (CDC). https://www.cdc.gov/drugoverdose/data/index.html
5. Assistant Secretary of Public Affairs (ASPA). (2019, September 4). About the Epidemic. HHS.Gov. https://www.hhs.gov/opioids/about-the-epidemic/index.html
6. U.S. Department of Health and Human Services. (2018, May 23). HHS Acting Secretary Declares Public Health Emergency to Address. HHS.Gov. https://www.hhs.gov/about/news/2017/10/26/hhs-acting-secretary-declares-public-health-emergency-address-national-opioid-crisis.html
7. Madras, B. K., Ahmad, N. J., Wen, J., Sharfstein, J., & Prevention, Treatment, and Recovery Working Group of the Action Collaborative on Countering the U.S. Opioid Epidemic. (2020). Improving Access to Evidence-Based Medical Treatment for Opioid Use Disorder: Strategies to Address Key Barriers Within the Treatment System. NAM Perspectives, 1–37.
8. Strayer, R. J., Hawk, K., Hayes, B. D., Herring, A. A., Ketcham, E., LaPietra, A. M., Lynch, J. J., Motov, S., Repanshek, Z., Weiner, S. G., & Nelson, L. S. (2020). Management of Opioid Use Disorder in the Emergency Department: A White Paper Prepared for the American Academy of Emergency Medicine. The Journal of Emergency Medicine, 58(3), 522–546.
9. Ling, W. (2012). Buprenorphine for opioid addiction. Pain Management, 2(4), 345–350.
10. Cisewski, D. H., Santos, C., Koyfman, A., & Long, B. (2019). Approach to buprenorphine use for opioid withdrawal treatment in the emergency setting. The American Journal of Emergency Medicine, 37(1), 143–150.
11. Velander, J. R. (2018). Suboxone: Rationale, Science, Misconceptions. The Oschner Journal, 18(1), 23–29.
12. Berg, M. L., Idrees, U., Ding, R., Nesbit, S. A., Liang, H. K., & McCarthy, M. L. (2007). Evaluation of the use of buprenorphine for opioid withdrawal in an emergency department. Drug and Alcohol Dependence, 86(2–3), 239–244.
13. D’Onofrio, G., O’Connor, P. G., Pantalon, M. V., Chawarski, M. C., Busch, S. H., Owens, P. H., Bernstein, S. L., & Fiellin, D. A. (2015). Emergency Department–Initiated Buprenorphine/Naloxone Treatment for Opioid Dependence. JAMA, 313(16), 1636.
14. Yale School of Medicine. (2018, September 24). ED-Initiated Buprenorphine. https://medicine.yale.edu/edbup/treatment/
15. Goodnough, A. (2018, August 20). This E.R. Treats Opioid Addiction on Demand. That’s Very Rare. New York Times. https://www.nytimes.com/2018/08/18/health/opioid-addiction-treatment.html
16. CA Bridge. (2021, May). Resources to Treat Substance Use Disorders. https://cabridge.org/tools/resources/
17. Hawk, K. F., D’Onofrio, G., Chawarski, M. C., O’Connor, P. G., Cowan, E., Lyons, M. S., Richardson, L., Rothman, R. E., Whiteside, L. K., Owens, P. H., Martel, S. H., Coupet, E., Pantalon, M., Curry, L., Fiellin, D. A., & Edelman, E. J. (2020). Barriers and Facilitators to Clinician Readiness to Provide Emergency Department–Initiated Buprenorphine. JAMA Network Open, 3(5), e204561.
18. Lowenstein, M. (2019, March 13). Starting Opioid Use Disorder Treatment in the Emergency Department. Leonard Davis Institute of Health Economics at the University of Pennsylvania. https://ldi.upenn.edu/healthpolicysense/starting-opioid-use-disorder-treatment-emergency-department
19. Kravitz-Wirtz, N., Davis, C. S., Ponicki, W. R., Rivera-Aguirre, A., Marshall, B. D. L., Martins, S. S., & Cerdá, M. (2020). Association of Medicaid Expansion With Opioid Overdose Mortality in the United States. JAMA Network Open, 3(1), e1919066.
20. Sharp, A., Jones, A., Sherwood, J., Kutsa, O., Honermann, B., & Millett, G. (2018). Impact of Medicaid Expansion on Access to Opioid Analgesic Medications and Medication-Assisted Treatment. American Journal of Public Health, 108(5), 642–648.
21. Practice Guidelines for the Administration of Buprenorphine for Treating Opioid Use Disorder. Federal Register. (2021, April 28). https://www.federalregister.gov/documents/2021/04/28/2021-08961/practice-guidelines-for-the-administration-of-buprenorphine-for-treating-opioid-use-disorder.
22. Become a Buprenorphine Waivered Practitioner. SAMHSA. (2021, May 5). https://www.samhsa.gov/medication-assisted-treatment/become-buprenorphine-waivered-practitioner.
23. Fiscella, K., Wakeman, S. E., & Beletsky, L. (2019). Buprenorphine Deregulation and Mainstreaming Treatment for Opioid Use Disorder. JAMA Psychiatry, 76(3), 229.
24. Auriacombe, M., Fatséas, M., Dubernet, J., Daulouède, J.-P., & Tignol, J. (2004). French Field Experience with Buprenorphine. American Journal on Addictions, 13(s1), S17–S28.

By: James Unverferth, PharmD, BCPS; Pharmacist Clinical Specialist

SSM Health St. Mary’s Hospital – St. Louis

Background

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.

By: Megan Musselman, PharmD, MS, BCPS, BCCCP, MSHP Research & Education Foundation

At the MSHP/ICHP Spring Meeting, the R&E Foundation presented Kat Lincoln, PharmD, BCPS, BCIDP with the MSHP Best Practice Award for her project entitled “Daptomycin weight-based dose optimization”. Olathe Medical Center implemented a dose optimization intervention that utilized adjusted body weight (AdjBW) for patients ≥ 130% of their ideal body weight (IBW) and actual body weight (ABW) for those < 100% IBW. The primary outcome was to determine if implementation of a weight –based dose optimization intervention was effective for the treatment of severe gram-positive infections infection. Secondary outcomes included adverse effects and costs associated with the new dosing protocol. The goals and specific aims for the program were to determine safety and efficacy of dosing daptomycin using AdjBW, decrease cost associated with this dosing strategy, and to develop criteria for use of daptomycin.

At the conclusion of the study, the average patient age was 60 years old with an average ABW of 97.25 kg. Of the patients included, 52.5% had a BMI ≥ 30 kg/m2 and 16.6% had a BMI > 40 kg/m2. The infection classification for daptomycin dosing is found in Table 1. In addition, 20% of patients were readmitted within 90 days due to infectious indications. Severity and type of infection attributed to persistence and higher rates of readmission.

The cost of daptomycin powder for injection is $0.11/mg. Patients with BMI ≥ 30 mg/k2 using AdjBW had a cost savings of $8,000 over 11 months. Patients treated using AdjBW accounted for 53% of orders, but only accounted for 27% of the total cost (Figure 1). The second most common dosing strategy used during the study period was ABW (27.1%) followed by 19.9% of patients being dosed by IBW (Figure 2).

In conclusion from this research project, patients treated using the dose optimization protocol were adequately dosed for treatment and pathogen eradication with minimal 90 day readmission rates. The following daptomycin dosing protocol maintained effectiveness and safety while reducing costs:

• ABW < 100% of patient IBW: Daptomycin dosed using ABW

• ABW ≥ 100-129% of patient IBW: Daptomycin dosed using IBW

• ABW ≥ 130% of patient IBW: Daptomycin dosed using AdjBW

If you have any questions about how Dr. Lincoln implemented her project, please email her at Kathryn.burnett@olathehealth.org.

By Nathan Hanson, PharmD, MS, BCPS; Healthtrust Supply Chain

“The best time to plant a tree is 20 years ago. The second best time to plant a tree is today.”  -Unknown

The 2021 Missouri Legislative Session has ended.  We could look at that fact and think that we are too late and missed an opportunity.  A more productive mindset is that we are right on time to get started for the 2022 session.  Now is the perfect time to begin learning or continue learning about the various processes that lead to change.  There are many ways to get involved, at the local, state, and Federal level.  This is true for the legislative process, for the regulatory process, and also for the associations in which we participate.  Here are some simple and practical ways that you can increase your ability to get involved for the next year and the next 20 years.

Local Involvement:

It is my opinion that you should know your mayor and your city council leaders.  Mark some time on your personal calendar to click around on your local government’s web site to learn who your mayor and City Council members are.  Find out when the meetings are, and consider attending one this year.  This may not have much of an impact on pharmacy, but I have found that the local government often has the biggest impact on our daily lives.  And learning about the government processes at the local level is a good training ground for the next level. 

State Involvement:

You should also know your state representative, your state senator, and your governor. The state government won’t be in session until January of 2022, but you can learn about your state representatives and senators right now.  Simply click on this link and type in your home address in the “Find Your Representative” box.  You could also look up the address of your workplace, so that you know the house and senate districts for both locations.  I recommend that you copy and paste this information into the document that you save in a folder marked “Involvement.”  You can use this document to capture information and ideas and keep it all in one place.  Then spend a few minutes clicking on the government web sites of your senator and representative to learn about their background, their committee membership, and the legislation they have sponsored or cosponsored.  If you are feeling very brave, you can spend 5 minutes making a phone call to their office.  In most cases you will speak to a staff member at their front desk or leave a voicemail.  Simply say that you are a hospital pharmacist, and you believe that patients will benefit any time that they are given greater access to the care that pharmacists can provide.  Then offer to be a resource for the senator or representative if they ever have a question about pharmacy related issues.  These small steps will help you to get involved, and they will show our elected officials that pharmacists are interested in the process.

If you have ideas for ways that the laws need to be changed so that you can take better care of patients, please let us know.  This is the time for brainstorming and information sharing, because bills generally need to be filed by December 1st.  We can be talking with our partners to see what will fit into the priorities for 2022. 

Federal Involvement:

You should know your representative and both of your senators, and you can find this information at the same website.  You can reach out to these leaders as well, but they’re certainly a little less available than the state leaders.  The best way to engage with the Federal centers and representatives is through the ASHP website.  Please take 5 minutes today to enroll on this website so that you can be poised and ready to respond when our responses are needed.

MHSP Involvement:

As we are kicking off the 2022 preparation, we would love to have your input.  If you aren’t already active on a committee please reach out.  We have a lot of exciting plans and a lot of goals we want to accomplish this year.  In the public policy committee we have formed task forces to accomplish these aims:

1.    Work toward obtaining pharmacist prescriptive authority
2.    Identify and disseminate advocacy topics
3.    Develop MSHP position statements for pertinent legislation
4.    Provide professional development

If you are interested in joining, please contact us! 

ASHP Involvement:

Each year the ASHP House of Delegates reviews a variety of policy statements.  You can see these policies here, and you can provide your input to the public policy committee or to the delegates directly.  There are also a lot of other ways to get involved out with your section or at ASHP Connect.

Plant Today!

Even if you didn’t get involved with legislative day this year, you can easily get involved next year.  If you missed your opportunity to weigh in on PBM restrictions, the PDMP bill, or various bills that allow patients better access to medications, you can rest assured that there will be plenty of opportunities next year.  Like trees, our progress as professionals can best be measured by the decade.  Make this the year where you begin to grow and change and step outside your comfort zone to make an impact for patients and our profession!  You may be surprised how much you can accomplish if you do. 

Don’t Miss What the Public Policy Committee Has Done!

http://www.moshp.com/Public-Policy/

By: Amanda Bernarde, PharmD; PGY-1 Pharmacy Resident

University of Missouri Health Care

Abbreviations: RSI = rapid sequence intubation; KPA = ketamine propofol admixture; ED= emergency department; SBP= systolic blood pressure; OR= odds ratio; CI= confidence interval; NEAR= National Emergency Airway Registry; TBI= traumatic brain injury; MAP = mean arterial pressure

Rapid sequence intubation (RSI) is a mainstay in critical care and emergency medicine to secure a patient’s airway.^1,2 Endotracheal intubation may be indicated if the patient: 1) cannot protect his/her airway, 2) has a risk of aspiration, 3) fails to adequately ventilate or oxygenate, or 4) has anticipated further or rapid decompensation leading to any of the other indications. To facilitate endotracheal tube placement, RSI requires use of sedatives and paralytics to minimize consciousness and to blunt the pathophysiologic response of airway manipulation, respectively. Ideal sedatives produce deep anesthesia with a rapid onset of 30 seconds or less.³ The paralytic agent should have a similar duration. Midazolam, propofol, ketamine, and etomidate are among some of the most common sedatives used in RSI. Though the goal of sedative medications is to augment easy manipulation of the airway, they are not without their own adverse effects, including peri-intubation hypotension.

Concerns for peri-intubation hypotension limit sedative options due to the potential increased risk of cardiac arrest, need for vasopressor support, and in-hospital and post-discharge mortality.^3-5 Etomidate, the gold standard sedative, displays hemodynamic neutrality when administered at a dose of 0.2-0.3 mg/kg, whereas midazolam and propofol have known risks of hypotension. Etomidate has potential adverse effects of adrenal suppression and lowering the seizure threshold, which makes it a suboptimal choice during RSI induction in patients presenting with sepsis, epilepsy, or traumatic brain injury (TBI) patients. Increased interest in exploring other RSI sedation options, particularly ketamine only and ketamine-propofol admixture (KPA) regimens, have been analyzed for use in these patient populations.

Mechanistically, ketamine at doses of 0.5-1 mg/kg increase catecholamine release while prohibiting its reuptake in the synaptic cleft.^3,6,7 In patients with sufficient circulating catecholamines, this leads to increased blood pressure. In contrast, patients with autonomic dysfunction, such as in sepsis, diabetic ketoacidosis, and myocardial infarction, exhibit decreased myocardial contraction and heart rate.⁸ Recent literature of ketamine use for sedation during RSI in hemodynamically unstable patients has shown mixed results (Table 1).

Table 1. Summary of hemodynamic effects of ketamine alone compared to other sedatives.

Ischimaru et al was the first study to establish ketamine’s potential hemodynamic neutrality during intubation of hemodynamically unstable patients.⁶ This prospective observational study from Japan found a statistically significant decrease in ketamine-induced hemodynamic derangement, defined as SBP ≤ 90 mmHg or ≥ 20% decrease in SBP, when compared with the combined comparator of either midazolam or propofol administration. Statistical significance held after adjustments for differences in demographics, primary indication (except in trauma patients), premedication use, and paralytic choice between the two study groups. From this analysis, authors concluded ketamine is superior to midazolam or propofol in maintaining stable hemodynamics during intubation. Of note, etomidate was not compared to ketamine in this study because it is not approved for use in Japan. Due to this difference, additional studies comparing ketamine to etomidate were required to potentially change practice in the United States.

A single large-scale, prospective, multicenter, observational cohort study was conducted by April et al comparing the incidence of peri-intubation hypotension of ketamine to etomidate for any indication.⁹ Using the NEAR study dataset, ketamine was found to have a statistically significant increase in peri-intubation hypotension incidence in comparison to etomidate. Doses chosen by the practitioner did not impact this outcome. This indicated that ketamine may not provide hemodynamic neutrality as the above study suggested. There were several challenges that limit this study’s generalizability to all populations, including the propensity to choose ketamine over etomidate for sepsis and traumatic brain injury (TBI) patients.

A subgroup analysis of NEAR study participants examined current use of etomidate compared to other sedatives and intubation-associated hypotension incidence of etomidate and ketamine.10 Etomidate was the most frequently used sedative in sepsis patients despite the concerns for its potential adrenal suppression. However, etomidate administration decreased and ketamine administration increased in sepsis patients when compared to nonsepsis patients. In this patient population, patients receiving ketamine did experience intubation-related hypotension more often than those administered etomidate. The hypotension was not sustained or significant as there was no statistical difference in need of vasopressor therapy or peri-intubation cardiac arrest between the two medications. The TBI patient cohort had similar findings that showed significant intubation-associated hemodynamic instability with ketamine when compared to other sedatives.¹¹ Unfortunately, analysis of emergency department or in-hospital use of ketamine for RSI in TBI patients is limited. Overall, in the setting of sepsis or TBI, ketamine does not provide beneficial hemodynamic outcomes, with mixed translation to need for vasopressors and incidence of peri-intubation cardiac arrest.

A novel approach to RSI induction was explored by Smischney et al in the KEEP-PACE trial.¹² Reduced dose etomidate (0.15 mg/kg) was compared to a ketamine-propofol admixture (KPA; 0.5 mg/kg of each component) for hemodynamic stability. Because of the novelty of this admixture, the purpose was to establish KPA’s superiority over reduced dose etomidate and reanalyze the mixture against the full etomidate dose if superiority was found. The primary endpoint, the change in mean arterial pressure (MAP) from baseline at 5 minutes post-induction, was not statistically significant (KPA vs etomidate: -3.3 mmHg vs -1.1 mmHg; p= 0.385). Additionally, there was no difference at 10 minutes, 15 minutes, or in average MAP area under the curve. Due to the lack of efficacy, KPA has not been compared to full-dose etomidate.

Despite the initial positive results suggesting ketamine as an alternative to etomidate for hemodynamically unstable patients during RSI, several multicenter, large-scale observational cohort studies have concluded otherwise. At present, etomidate remains the gold standard for induction, particularly in patients who are hemodynamically unstable or have RSI-indications that could quickly decompensate. Nevertheless, the need remains for a hemodynamically neutral induction agent that does not manipulate the adrenal system or lower the seizure threshold, which continues to be the main concerns with universal etomidate use.

References

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2. Driver BE, Klein LR, Prekker ME, et al. Drug order in rapid sequence intubation. Acad Emerg Med. 2019;26(9):1014-1021.
3. Hamilton JP. Rapid-sequence intubation and the role of the emergency department pharmacist. Am J Health Syst Pharm. 2011;68(14):1320-1330.
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5. April MD, Arana A, Reynolds JC, et al. Peri-intubation cardiac arrest in the emergency department: a National Emergency Airway Registry (NEAR) study. Resuscitation. 2021;S0300-9571(21)00097-6.
6. Ishimaru T, Goto T, Takahashi J, et al. Association of ketamine use with lower risks of post-intubation hypotension in hemodynamically-unstable patients in the emergency department. Sci Rep. 2019;9(1):17230.
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9. April MD, Arana A, Schauer SG, et al. Ketamine versus etomidate and peri-intubation hypotension: a National Emergency Airway Registry study. Acad Emerg Med. 2020;27(11):1106-1115.
10. Mohr NM, Pape SG, Runde D, Kaji AH, Walls RM, Brown CA. Etomidate use is associated with less hypotension than ketamine for emergency department sepsis intubations: a NEAR cohort study. Acad Emerg Med. 2020;27(11):1140-1149.
11. Fouche PF, Meadley B, St Clair T, et al. The association of ketamine induction with blood pressure changes in paramedic rapid sequence intubation of out-of-hospital traumatic brain injury. Acad Emerg Med. 2021. Epub ahead of print.
12. Smischney NJ, Nicholson WT, Brown DR, et al. Ketamine/propofol admixture vs etomidate for intubation in the critically ill: KEEP PACE randomized clinical trial. J Trauma Acute Care Surg. 2019;87(4):883-891.