• 03 Aug 2021 1:42 PM | Anonymous

    By: Kelly Williams & Jenny Ohnesorge, Pharm.D. Candidates 2023; UMKC SSHP Chapter Presidents

    Despite living and learning in a pandemic, the leadership of UMKC’s SSHP across three campuses (Kansas City, Columbia, and Springfield) persevered by innovating new ways to connect to students and the community. In the Fall of 2020, there were still many unknowns to the pandemic, but the executive teams pushed on and planning was underway for virtual events, a change from previous years. The year kicked off with the New Student Orientation on the lawn of the Health Sciences Building and executive team members were able to talk about what ASHP and SSHP can do for its members. In September, Residency Roundtable was held for the first time ever via Zoom. UMKC’s Residency Roundtable 2020 consisted of discussion-based breakout rooms with the Residency Program Directors and current residents, a keynote presentation, and information about PhorCAS and Midyear. We were able to host a variety of programs from sites that would otherwise be impossible in-person. Many of the programs that attended Residency Roundtable were not from Missouri, but states such as Nebraska, Iowa, Arkansas, Kansas, and Texas. The event was deemed a success from student attendees and the SSHP executive board alike, with talks to continue hosting Residency Roundtable virtually in order to reach a more diverse array of residency programs. Next, in October, we were able to host the Clinical Skills Competition via Zoom as well, where 12 teams of two students competed. The Clinical Skills Competition was held on two separate days, the first day consisting of a written case workup by each team, and the second day consisting of an oral presentation from three semi-finalist teams. Both days were judged by a panel of pharmacy residents. Similar to Residency Roundtable, the Clinical Skills Competition proved to be very successful as it also transitioned to a new virtual structure, with talks to continue this format going forward.

    In both the fall and spring, UMKC’s SSHP held monthly general meetings with speakers from health-systems across Missouri. Topics covered included patient cases and general discussion of the day to day activities as a health-system pharmacist. Additionally, we were excited to host MSHP President Dr. Davina Dell as she presented over ASHP’s Practice Advancement Initiative (PAI) 2030. Furthermore, students were encouraged to attend community service events held at the three campuses; such events consisted of volunteering at Harvester’s and Habitat for Humanity and cleaning up trash alongside roads and highways

    The Columbia SSHP team was able to coordinate one event with MMSHP in the Fall of 2020, including food trucks, drinks, and trivia at a local eatery. Columbia’s SSHP team was also able to arrange a fundraiser selling embroidered UMKC School of Pharmacy jackets and quarter-zips, a feat that raised over $450 for the UMKC SSHP chapter. We hope to continue this fundraiser in the coming years.

    We are excited to once again get creative with our events in the Fall. We look forward to incorporating more virtual events into our schedule, including Residency Roundtable and the Clinical Skills Competition. This summer, the 2021-22 SSHP Executive Team will be hard at work to bring the most valuable experience to its student members. We are very thankful for MSHP’s involvement with SSHP across the three campuses and wish you a restful remainder of your summer!

  • 03 Aug 2021 1:40 PM | Anonymous

    By: Leah Blocker, PharmD Candidate 2023; SSHP President

    At St. Louis College of Pharmacy, our SSHP chapter holds many events that aim to advance and educate pharmacy students. In addition to our ongoing Mentor/Mentee program, some of the events we held this past year included Curriculum Vitae Writing and Review, Resident and Residency Director Roundtables, and a Medical Marijuana Lunch ‘n Learn.

    Our Mentor/Mentee Program is an annual matching program we hold that connects undergraduate or P1 students with professional students. Mentors are able to guide their mentees through their transition from the undergraduate program to the professional program at STLCOP. This program helps younger students face the many new challenges that are associated with the professional program, such as a heavier workload and more independent studies. The mentors in our program are there to offer advice.  Not only that, but our mentor-mentee program also opens up discussion about post-graduate opportunities, such as residency, which many younger students have not yet had time to explore.

    At our Curriculum Vitae Writing and Review events, we aim to educate students on how to create or improve their professional curriculum vitae (CV). CV’s are one of the most important ways a student can promote themselves to residency programs or future job opportunities. At STLCOP, one of our professors, Dr. Jack Burke, leads the CV Writing event. He plays a key role in educating students on the most important aspects of a CV and how to properly structure a CV. For our CV Review event, students were able to submit their CV to us and receive feedback from one of the pharmacist members of StLSHP. This allowed students the opportunity to have a pharmacist review their CV and make suggestions to help improve their chances of standing out in the future.

    Our Resident and Residency Director Roundtable events aim to connect professional students with current pharmacy residents and residency directors in the St. Louis area. The goal is to educate students on the different opportunities available to them after graduation, as well as enlighten them about what residency is like and what to expect. Current residents and residency directors are able to provide students with insight and tips, and students have an open platform to ask questions and receive direct answers.

    Lastly, a new event we held this year included a Medical Marijuana Lunch ‘n Learn. With the ever-changing advancements in legislature and medicine, it is important to keep students up to date and educated on significant topics, such as medical marijuana and its uses in the pharmacy field. Students are only briefly exposed to the topic of medical marijuana in our professional studies, so by offering this event, we hoped to expose more students to the topic in order to better prepare them for their future.

  • 03 Aug 2021 1:19 PM | Anonymous
    By: Elizabeth Nash, St. Louis College of Pharmacy Pharm.D. Candidate 2022 and Morgan Luttschwager Rose, MBA, St. Louis College of Pharmacy Pharm.D. Candidate 2022

    Mentor: Michelle Jeon, Pharm.D., BCACP, Assistant Professor of Pharmacy Practice, St. Louis College of Pharmacy at UHSP

    Heparin-induced thrombocytopenia (HIT) is an unusual drug reaction involving heparin exposure. Overall, HIT epidemiology is not well documented; however, reports indicate it will occur in about 0.1-0.5% of patients on heparin therapy including low molecular weight heparin (LMWH) and unfractionated heparin (UF). Based on a population study conducted in 2018, the incidence of HIT diagnosis are relatively low. HIT seems to be more common after cardiac surgeries compared to after orthopedic surgeries.1

    Once HIT occurs, the most common complication is thrombosis, occurring in 30% of cases, with bleeding occurring in 6.2%. In patients that experience bleeding, 25% of patients do not survive regardless of treatment.1

    The pathophysiology of HIT (Figure 1) was identified in the early 1970s, nearly 20 years after the first reported case. The prominent players in the pathophysiology of HIT include platelet factor 4, heparin, platelets, monocytes, factors VII, IX, X, and thrombin.

    Once heparin is administered, it binds to naturally occurring platelet factor 4 due to ionic forces—this binding halts heparin’s action. The immune system responds by creating IgG antibodies that attack the PF4/heparin complex. The immunocomplex then binds to the surface of platelets and monocytes. This binding triggers their activation through the cross-linking of FcgIIA receptors. Platelet activation then leads to aggregation and stimulation of procoagulant activity. Monocyte activation stimulates tissue factor (TF) generation. TF binds with factor VII to activate factors IX and X, which in turn stimulate thrombin formation. Thrombin leads to known clinical problems associated with HIT, such as pulmonary embolism, mesenteric ischemia, ischemic limb necrosis, acute myocardial infarction, and stroke.2 

    Figure 1. Pathophysiology of heparin-induced thrombocytopenia2

    Risk Factors
    All patients receiving any form of heparin should to be monitored for HIT with routine labs including platelets. However, there are some specific scenarios in which increased risk may be present and extreme caution should be used. Risk factors for HIT include:

    • Heparin therapy used for a duration longer than five days, regardless of dose or indication
    • Type of heparin used, unfractionated heparin carries the largest risk
    • Surgical and trauma patients
    • Female patients3
    • Increasing age beyond the age of 50 years old1
    • COVID-19 infection - Further information in “COVID-19 Considerations”4,5,6

    Patients under these circumstances may require closer monitoring; however, there is still a risk for HIT in patients who do not have these risk factors.

    Diagnosis and Clinical Presentation
    Although HIT is rare, patients with suspected signs and symptoms should be evaluated for probability of the disease. As indicated in Figure 2, the 4Ts test considers thrombocytopenia, timeframe of platelet decreasing, thrombosis, and other causes of thrombocytopenia. If these tests reveal intermediate or high probability, an immunoassay, which identifies antibodies against PF4 or heparin should be conducted. If the immunoassay is positive, a functional platelet activation assay (e.g. serotonin release assay) should subsequently be performed, which shows antibodies that specifically induce heparin-dependent platelet activation3. If again positive, HIT is likely and treatment options should be considered. Typical clinical presentation of HIT includes platelet count decreased from baseline by greater than 50% and platelet nadir greater than or equal to 20,000/mm2. Patients with HIT typically have an onset within 5-14 days or less than one day with recent heparin exposure3. These patients may also have a confirmed thrombosis, necrosis of the skin at injection site, adrenal hemorrhage, or anaphylactoid reaction after heparin bolus. Patients with suspected HIT should have no other probable causes of thrombocytopenia.  

    Figure 2. Diagnosis for HIT3

    Treatment and Management
    The most critical information for practicing pharmacists regarding HIT is perhaps the treatment and management. Patients with HIT should be treated with non-heparin anticoagulants. The American Society of Hematology5 (ASH) suggests argatroban, bivalirudin, fondaparinux, or a direct-acting oral anticoagulant (DOAC). Patient-specific factors such as comorbidities, ease of administration, cost, route, etc., play a role in helping to select the best medication. If the patient is clinically stable, treatment with fondaparinux or any of the DOACs are best due to the ease of administration and the lack of routine labs required to monitor for safety. In situations where a short-acting anticoagulant is needed – such as in critical illness, increased bleed risk, or the potential for an urgent procedure – argatroban or bivalirudin are ideal. DOACs should be avoided in the case of life or limb-threatening thrombosis because they have not been thoroughly tested in this population. In a matter of such thrombosis, argatroban, bivalirudin, or fondaparinux are recommended for use. If patients also have moderate to severe hepatic dysfunction – defined as Child-Pugh Class B and C – bivalirudin, or fondaparinux are recommended over other options. If necessary, a lowered dose of argatroban may be appropriate in the case of hepatic impairment.3

    Monitoring Parameters
    HIT requires monitoring for signs and symptoms of thrombosis, bleeding and platelet recovery no matter which therapy option is chosen. Baseline aPTT levels should be drawn, if possible, to establish when thrombin levels have returned to normal. Several treatment options rely on platelet levels to determine duration of therapy. Signs and symptoms of bleeding such as bruising, weakness, and decreased blood pressure should be monitored daily. Patients diagnosed with HIT and a hemorrhage have a poor prognosis, with a 25% mortality rate regardless of treatment. The best chance to counter those odds is to catch the bleed early on with close monitoring.

    Drug-specific monitoring parameters can vary, especially between the newer DOACs and older agents. DOACs typically require less laboratory monitoring, which can be favorable for patients.

    COVID-19 Considerations
    The pathology of heparin-induced thrombocytopenia relies significantly on the platelet factor 4/heparin (PF4/H) complex and the antibodies developed against it. In the case of patients infected with the SARS-CoV-2 virus, the presence of these antibodies is increased.4, 5 Once infected, patients develop antibodies against the COVID-19 virus; however, these antibodies resemble the PF4/H antibodies so closely they can activate the B cells associated with HIT. Thrombotic complications associated with COVID-19 infection, therefore, share pathology with HIT. The SARS-CoV-2 infection is strongly related to thromboembolic events, perhaps due to the resemblance of the antibodies, making anticoagulation therapy common in hospitalized patients. When using heparin as anticoagulant therapy in infected patients, extreme caution should be used as the risk for HIT is increased.5

    Role of a Pharmacist
    Pharmacists can significantly impact the treatment of heparin-induced thrombocytopenia; they are on the front line to recognize the drug-induced reaction of HIT. Pharmacists should determine whether or not non-heparin products are an appropriate therapy for anticoagulant use. The risk factors of HIT could guide treatment selection and the level of monitoring needed. Pharmacists can use patient-specific factors to choose the best anticoagulation therapy for a patient. Pharmacists can also recognize when heparin is in lower concentrations in products such as heparin flushes, hematopoietic stem cell products, some total parenteral nutrition products, and prothrombin complex. As the drug experts, pharmacists can be the first to identify someone has HIT by evaluating side effects of the drug. Pharmacists should participate in an interdisciplinary approach to help manage HIT with exemplary patient-centered care.


    1. Dhakal B, Kreuziger LB, Rein L, et al. Disease burden, complication rates, and health-care costs of heparin-induced thrombocytopenia in the USA: a population based study. Lancet Haematol. 2018;5(5):e220-e231.
    2. Patriarcheas V, Pikoulas A, Kostis M, Charpidou A, Dimakakos E. Heparin-induced thrombocytopenia: pathophysiology, diagnosis and management. Cureus. 2020;12(3):e7385.
    3. Pishko AM, Linkins LA, Warkentin TE, Cuker A. Diagnosis and management of heparin-induced thrombocytopenia (HIT) a pocket guide for the clinician. Am Soc of Hematology. 2018;2(22):3226-3256.
    4. Zhu W, Zheng Y, Yu M, et al. SARS-CoV-2 receptor binding domain-specific antibodies activate platelets with features resembling the pathogenic antibodies in heparin-induced thrombocytopenia. Research Square. 2021;rs-3.
    5. Favaloro EJ, Henry BM, Lippi G. The complicated relationships of heparin-induced thrombocytopenia and platelet factor 4 antibodies with COVID-19. Int J Lab Hematol. 2021;00:1-12.
    6. Madala S, Krzyzak M, Dehghani S. Is COVID-19 an independent risk factor for heparin-induced thrombocytopenia. Cureus. 2021;13(2):e13425.
    7. Argatroban. Packa a pocketge Insert. LGM Pharma. 2011.
    8. Beiderlinden M, Treschan TA, Görlinger K, et al. Argatroban anticoagulation in critically ill patients. Ann Pharmacother. 2007;41(5):749-54.
    9. Bivalirudin. Package Insert. International Technidyne Corporation. 2016.
    10. Fondaparinux. Package Insert. GlaxoSmithKline. 2010.
    11. Agnelli G, Buller HR, Cohen A, et al. AMPLIFY investigators. oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808.
    12. Eliquis. Package Insert. Bristol-Myers Squibb Company and Pfizer Inc. 2021.
    13. Pradaxa. Package Insert. Boehringer Ingelheim Pharmaceuticals. 2015.
    14. Xarelto. Package Insert. Janssen Pharmaceuticals. 2016.
  • 03 Aug 2021 11:51 AM | Anonymous

    By: Jaynika Patel, PharmD Candidate 2023; University of Health Sciences and Pharmacy at St. Louis College of Pharmacy, Saint Louis, Missouri

    Mentor: Priyam Patel, PharmD; Aurora St. Luke’s Medical Center, Milwaukee, Wisconsin

    Obesity is a prevalent condition in the United States (U.S.) with nearly one in every three adults being affected.1 The body mass index (BMI) is utilized to determine the weight classification of an individual and can be calculated by dividing the weight in kilograms by the height in meters squared. Obesity is defined as a BMI of 30.0 kg/m2 or above and is further classified into three subcategories: class I (BMI 30-34.9 kg/m2), class II (35-39.9 kg/m2), and class III (≥ 40 kg/m2). Morbidly obese patients are considered Class III based on their BMI.

    Obesity presents as a risk factor for venous thromboembolism (VTE).2 Venous thromboembolism is a serious, yet preventable medical condition which refers to blood clots in the veins and could lead to a serious illness or death.3 It is estimated that the annual incidence of VTE in the U.S is 1 to 2 per 1000 of the population.3 Due to the high morbidity and mortality risk, the prevention and treatment of VTE have become a growing concern.

    Per the American College of Chest Physicians (CHEST) guidelines, the favorable treatment option for patients with VTE and no cancer diagnosis are direct oral anticoagulants (DOACs) over vitamin K antagonist (VKA) therapy.4 However, the guideline by the Scientific and Standardization Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) advises that DOACs should not be administered for BMI greater than 40 kg/m2 or weight greater than 120 kg due to inadequate drug exposure, short half-lives, and lower peak concentrations in this patient population.5 The remainder of this article will evaluate landmark trials and recent studies followed by the key takeaways.

    Landmark Trials and Recent Studies
    Each DOAC, supported by its landmark trial(s), has been evaluated for its efficacy and safety in the treatment of VTE. The outcomes measured in these trials include, but are not limited to, recurrence of VTE and major bleeding. The results of these studies concluded that DOACs in VTE are as effective for anticoagulation as VKA, such as warfarin.

    One limitation, as it pertains to this article, is that these landmark trials were conducted in a general population, which had a low enrollment of morbidly obese patients. The enrollment for the highest weight/BMI categories reported in these trials is summarized in Table 1. Recent studies aim to determine the efficacy and safety of DOAC use in morbidly obese patients.  

    Elshafei et al. performed a systematic review followed by a meta-analysis of trials that compared efficacy and safety of DOAC use to warfarin for acute VTE in morbidly obese patients.12 Four observational studies assessed the efficacy and safety outcomes. The primary efficacy outcome of VTE recurrence rate in morbidly obese patients determined that DOAC use compared to warfarin was non-inferior (OR 1.07, 95% CI 0.93 to 1.23, Q=1.45, I2=0%) with a low I2, indicating the results were homogenous. In regard to major bleeding events, the analysis identified a non-significant risk reduction by 20% in the DOAC group (OR 0.80, 95% CI 0.54 to 1.17, Q=0.16, I2=0%). This study provided evidence that DOAC use as an alternative to warfarin in morbidly obese patients is effective and safe.

    Spyropoulos et al. conducted a retrospective 1:1 propensity score-matched cohort study that analyzed morbidly obese patients diagnosed with a VTE who received rivaroxaban or warfarin.13 Two analyses were conducted in this study to observe continual anticoagulant use: intent-to-treat (ITT) and on-treatment (OT). In the ITT analysis, the risk of recurrent VTE in the rivaroxaban group (16.8%) versus the warfarin group (15.9%) was not significantly different (OR 0.99, 95% CI 0.85 to 1.14, P=0.8443). However, major bleeding events in the treatment group (1.8%) in comparison to the warfarin group (2.5%) were significant lower (OR 0.66, 95% CI 0.45 to 0.98, P = 0.0388). In the OT analysis, the risk of recurrent VTE for rivaroxaban (14.8%) versus warfarin (13.4%) was not statistically significant (OR 1.02, 95% CI, 0.87 to 1.20, P=0.8343). Major bleeding events for rivaroxaban (1.4%) and warfarin (1.8%) also did not occur at a statistically different rate (OT: OR 0.75, 95% CI 0.47 to 1.19, P=0.2266). The two analyses provided consistent results in concluding that rivaroxaban has comparable efficacy to warfarin in this study population.

    Coons et al. also performed a retrospective matched cohort study analyzing the effectiveness and safety of DOACs for acute VTE treatment in morbidly obese patients in comparison to warfarin.14 The primary outcome was the recurrence of VTE within 12 months after the index admission date. Of the patients with a diagnosis of acute VTE and weight threshold of 100 kg to 300 kg, 632 patients had received a DOAC, while 1208 patients had received warfarin. Rivaroxaban was the primary DOAC administered, representing 91.8% of the patient population. The recurrence of VTE occurred in 6.5% of patients in the DOAC group versus the 6.4% of patients in the warfarin group, which was not a statistically significant difference (P=0.93). The incidence of the primary outcome in the apixaban, rivaroxaban, and warfarin groups were 2.1%, 2%, and 1.2%, respectively (P=0.74). Bleeding events in the DOAC group (1.7%) and warfarin group (1.2%) were also not statistically significant (P=0.31). Based on the data, the authors of the study support the treatment of acute VTE in morbidly obese patients with DOACs.

    A retrospective single-center cohort study by Patil et al. analyzed the efficacy and safety of DOACs versus warfarin in the morbidly obese Veteran patient population.15 In the DOAC group, apixaban was administered to 61.68% of the patients, rivaroxaban to 32.71%, and dabigatran to 5.61%. The primary outcome measure was a composite of VTE and stroke/transient ischemic attack. The results of the annual incidence rate of the primary outcome were not statistically significant between the DOAC group (1.61%) and warfarin group (3.91%) (RR 2.436, 95% CI 0.776 to 10.08, P=0.1543). The secondary outcome measuring major bleeding based on the ISTH guidelines had similar annual incidence rates between the two groups (warfarin: 3.13% vs. DOACs: 3.21%, RR 0.97, 95% CI 0.36 to 2.75, P=0.9438). Overall, the study results demonstrated that the administration of DOACs in comparison to warfarin is a viable alternative in morbidly obese patients. 

    The recent studies discussed above suggest that DOAC use in the treatment of VTE in morbidly obese patients may be efficacious in preventing recurrent VTE. The non-inferiority studies still hold warfarin to be a viable treatment option for patients. Regarding safety, DOACs demonstrated similar or slight variations in the rates of bleeding events compared to warfarin which may be contributed from patient-specific factors or inconsistent monitoring. The results of these studies were strengthened by the study design which included a diverse population, relevant subgroup of patients, and large databases for research. 

    One major limitation found amongst the retrospective studies was that they relied on accurate documentation that may not have considered other factors at that time, such as specific comorbidities or concomitant use of other high bleeding risk medications. Additionally, the predominance of one DOAC in a study analyzing all DOACs does not provide a balanced comparison. Thus, prospective clinical trials studying the effects of all DOACs for the treatment of VTE in morbidly obese patients are needed to determine which DOAC is superior and most appropriate to recommend. 


    1. Defining adult overweight & obesity. Centers for Disease Control and Prevention. https://www.cdc.gov/obesity/adult/defining.html. Updated June 7, 2021. Accessed June 9, 2021.
    2. Overweight and obesity. National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/health-topics/overweight-and-obesity. Accessed June 3, 2021.
    3. What is venous thromboembolism? Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/dvt/facts.html. Updated February 7, 2020. Accessed June 1, 2021.
    4. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):314-352.
    5. Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14(6):1308-1313.
    6. Schulman S, Kearon C, Kakkar AK, et al.; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-52.
    7. Schulman S, Kakkar AK, Goldhaber SZ, et al.; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-72. 
    8. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-510. 
    9. EINSTEIN–PE Investigators, Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-97.
    10. Agnelli G, Buller HR, Cohen A, et al.; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808.
    11. Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-15.
    12. Elshafei MN, Mohamed MFH, El-Bardissy A, et al. Comparative effectiveness and safety of direct oral anticoagulants compared to warfarin in morbidly obese patients with acute venous thromboembolism: systematic review and a meta-analysis. J Thromb Thrombolysis. 2021;51(2):388-396.
    13. Spyropoulos AC, Ashton V, Chen YW, et al. Rivaroxaban versus warfarin treatment among morbidly obese patients with venous thromboembolism: Comparative effectiveness, safety, and costs. Thromb Res. 2019;183:159-166.
    14. Coons JC, Albert L, Bejjani A, Iasella CJ. Effectiveness and safety of direct oral anticoagulants versus warfarin in obese patients with acute venous thromboembolism. Pharmacotherapy. 2020;40(3):204-210.
    15. Patil T, Lebrecht M. A single center retrospective cohort study evaluating use of direct oral anticoagulants (DOACs) in morbidly obese veteran population. Thromb Res. 2020;192:124-130. 
  • 03 Aug 2021 11:41 AM | Anonymous

    By: Michelle Tulchinskaya, Elena Stroman, and Katherine Nguyen; PharmD. Candidates

    Mentor: Anastasia L. Armbruster Pharm.D., FACC, BCPS, BCCP

    Since 2017, new therapies for Heart Failure with Reduced Ejection Fraction (HFrEF) have emerged reducing both mortality and hospitalizations for heart failure in this population. In particular, two drug therapies have emerged: angiotensin receptor-neprilysin inhibitors (ARNIs), and sodium-glucose cotransporter-2 inhibitors (SGLT2s). Overall, ARNIs, SGLT2s, and other guideline directed medical therapy (GDMT) are underutilized. CHAMP-HF has exhibited the underutilization of these medications.1 Specifically sacubitril/valsartan (Entresto®), has been underutilized even after the 2016 ACC/AHA/HFSA Focused Update on HF included it as a Class I recommendation for patients with HFrEF.2 In outpatient settings, 86.1% of patients without contraindications did not receive sacubitril/valsartan. Patients with the following characteristics were less likely to receive treatment; older age, Hispanic ethnicity, chronic insufficiency, and higher EF (p ≤ 0.009). Patients with higher systolic blood pressure and a history of hypertension were associated with achieving a ≥50% target dose (all p ≤ 0.037).1

    Traditionally, angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) have been first line therapies for patients with Stage C HFrEF. The 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment is the first document to prefer the usage of ARNIs for patients with Stage C HFrEF over ACE-Is/ARBs.2 Neprilysin, also known as neutral endopeptidase, is a zinc-dependent metalloprotease that inactivates several vasoactive peptides, such as natriuretic peptides, adrenomedullin, bradykinin, and substance P, each of which has an important role in the pathogenesis and progression of HF.2 As demonstrated in the PARADIGM-HF trial, sacubitril/valsartan was associated with reduced hospitalizations, morbidity, and mortality in these patients compared to enalapril.3 The composite of death from cardiovascular causes or hospitalization for heart failure occurred in 914 patients (21.8%) in the sacubitril/valsartan group and 1117 patients (26.5%) in the enalapril group (HR in LCZ696 group: 0.80; 95% CI 0.73 - 0.87; P<0.001).4 Due to this pivotal trial and following guideline recommendations, the preference is to start patients on an ARNI at the diagnosis of Stage C HFrEF, transition patients from an ACE-I or an ARB, or start patients that have not been given an ARNI, ACE-I, or ARB. Recent data from clinical studies, along with aggregate clinical experience, suggest that directly initiating an ARNI, rather than a pretreatment period ACE-I/ARBs, is a safe and effective strategy.2 In the PIONEER-HF trial, it was concluded that sacubitril/valsartan’s efficacy and safety was consistent across dose levels in hemodynamically stable patients with advanced decompensated heart failure. In the randomized, double-blind, active-controlled trial sacubitril/valsartan versus enalapril, there was no heterogeneity across dose levels in the effects of sacubitril/valsartan on the reduction of NT-proBNP, reduction of cardiovascular death, rehospitalization, or pre-specified adverse events.5

    Although it is recommended to use an ARNI, ideal timing of initiation and rate of titration are frequently discussed. Many providers are concerned that patients will not be able to tolerate target dose due to adverse effects such as hyperkalemia, hypotension, cardiac failure, dizziness, renal impairment, angioedema, and cardiac failure. A randomized, multicenter, open-label study comparing two different treatment initiation regimens of sacubitril/valsartan, concluded that it was feasible for about half of the patients to achieve target dose within 10 weeks. In the TRANSITION trial, about half of the HF patients reached the recommended target dose in 10 weeks (relative RR 0.90; 95% CI 0.79 - 1.02), and over 86% were able to maintain any dose for at least  2 weeks leading to week 10 (relative RR 0.96; 95% CI 0.92 - 1.01).6 When obtaining full dose, it was noted that adverse effects of hyperkalemia, hypotension, cardiac failure, dizziness, renal impairment, angioedema, and cardiac failure were low. These adverse events were reasons for patients’ discontinuation of sacubitril/valsartan as well.6 It was found that a better tolerability profile was obtained when the uptitration was done gradually and that patient’s tolerability was higher when baseline adverse effects and labs of the patients were taken into account. Another multicenter, randomized, open-label, parallel‐group study found that a more gradual/conservative uptitration can increase the chance of attaining the target dose of sacubitril/valsartan in patients transitioning from lower doses of ACEI/ARBs.7 Additionally, it was found that the majority of patients (>80%) with SBP of ≥100 mmHg achieved and maintained the target dose of sacubitril/valsartan if the treatment was titrated gradually.8 A gradual dose increase included patients on a low dose of 24 mg/26 mg twice per day, followed by a titration up to 97 mg/103 mg twice per day over a 3 or 6 week period.8 These findings suggest that low SBP should not prevent clinicians from considering the initiation of sacubitril/valsartan.

    The mortality benefit of sacubitril/valsartan for HFrEF patients is notable as described in the PARADIGM-HF trial, but many patients struggle with access to the life-saving medication due to the high cost. Sacubitril/valsartan is covered by Medicare Part D, but the out-of-pocket cost can be more than $1,600 a year for patients. In a study conducted by DeJong, et al., more than 2,000 Medicare Part D plans were analyzed. While all plans fully covered sacubitril/valsartan, the results concluded that the average cost-sharing for a 30-day supply of an ARNI during the coverage period was $57, as opposed to a range of $2 - 5.00 for other heart failure medications such as ARBs, beta-blockers, and loop diuretics. The study estimated the subjects’ projected annual out-of-pocket costs to be $1,685, of which $1,632 of $1,685 (96.9%) would be attributable to the ARNI.9  Although Medicare Part D provides coverage for sacubitril/valsartan, patients would still be left with a considerable amount of out-of-pocket costs.

    An additional analysis of the effectiveness and value of sacubitril/valsartan, conducted by Ollendorf, et al., looked at the lifetime cost-effectiveness of sacubitril/valsartan relative to ACE-I therapy. The analysis showed that the ACE-I had averages of 5.56 quality-adjusted life years (QALYs) and total costs of $123,578, while sacubitril/valsartan produced an additional 0.57 QALY and an additional $29,138 in costs.10 This shows that cost-effectiveness would exceed $100,000 per QALY gained if the benefits of sacubitril/valsartan over enalapril persist for 3.3 years.10 Another study by Gaziano, et al. examined the cost-effectiveness of sacubitril/valsartan in comparison to enalapril in HFrEF patients. The study estimated that there would be 220 fewer hospital admissions per 1000 patients with heart failure treated with sacubitril/valsartan vs. enalapril over 30 years and calculated sacubitril/valsartan’s incremental cost-effectiveness ratio of US $45,017 per QALY gained.11 These findings concluded that utilization of sacubitril/valsartan could result in more QALYs gained, prevention of premature death, as well as significant cost-savings through avoided hospitalizations.

    There is sufficient evidence that exhibits sacubitril/valsartan’s benefit in HFrEF therapy, and updated guidelines now prefer the usage of ARNI. Sacubitril/valsartan has demonstrated a decrease in hospitalizations due to HFrEF in comparison to ACE-I/ARBs, in addition to cost-savings. Though there are concerns for tolerability of sacubitril/valsartan, it can potentially be avoided with a gradual uptitration to target dose. It would be beneficial to use sacubitril/valsartan over ACE-I/ARBs unless limited by contraindications, tolerability or cost limitations.


    1. Greene SJ, Butler J, Albert NM, DeVore AD, et al. Medical therapy for heart failure with reduced ejection fraction: The CHAMP-HF Registry. J Am Coll Cardiol. 2018 Jul 24;72(4):351-366.
    2. 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the american college of cardiology solution set oversight committee. J Am Coll Cardiol 2021;Jan 11
    3. Myhre PL, Vaduganathan M, Claggett B, et al. B-type natriuretic peptide during treatment with sacubitril/valsartan: the PARADIGM-HF trial. J Am Coll Cardiol. 2019;73:1264–72.
    4. McMurray JJ, Packer M, Desai AS, et al. PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004.
    5. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380(6):539-548.
    6. Wachter R, Senni M, Belohlavek J, et al. Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study. Eur J Heart Fail. 2019;21(8):998-1007.
    7. Senni M, McMurray JJ, Wachter R, et al. Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail. 2016;18(9):1193-1202.
    8. Senni M, McMurray JJV, Wachter R, et al. Impact of systolic blood pressure on the safety and tolerability of initiating and up-titrating sacubitril/valsartan in patients with heart failure and reduced ejection fraction: insights from the TITRATION study. Eur J Heart Fail. 2018;20(3):491-500.
    9. DeJong C, Kazi DS, Dudley RA, Chen R, Tseng CW. Assessment of national coverage and out-of-pocket costs for sacubitril/valsartan under Medicare Part D. JAMA Cardiol. 2019;4(8):828-830.
    10. Ollendorf DA, Sandhu AT, Pearson SD. Sacubitril-valsartan for the treatment of heart failure: effectiveness and value. JAMA Intern Med. 2016;176(2):249–250.
    11. Gaziano TA, Fonarow GC, Claggett B, et al. Cost-effectiveness analysis of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction. JAMA Cardiol. 2016;1(6):666–672.
  • 03 Aug 2021 11:39 AM | Anonymous

    By: Ethan Cowell, PharmD Candidate 2022; University of Health Sciences and Pharmacy in St. Louis

    Mentor: Joseph Van Tuyl, PharmD, BCCP; Assistant Professor of Pharmacy Practice/Pharmacy Clinical Specialist – Cardiology; University of Health Sciences and Pharmacy in St. Louis/St. Louis University Hospital

    Heart failure (HF) affected 6 million adults in the United States from 2015 to 2018 and costed approximately $30.7 billion dollars in 2012 alone.1  Economic estimates predict the total cost of HF will increase to $69.8 billion by 2030.1  Costs are primarily due to hospitalizations to treat HF and the comorbidities that commonly accompany this disease state. In 2014, the projected mean cost of primary HF hospitalizations was $11 billion (approximately $11,552 per hospitalization).2

    HF can be exacerbated by many comorbidities including iron deficiency, which is defined as a serum ferritin <100 mcg/L or serum ferritin 100 to 300 mcg/L with a transferrin saturation (TSAT) <20%.3  Iron deficiency may be prevalent in up to 21% HF patients with anemia, and iron deficiency may be present regardless of the presence of anemia.3, 4 Iron deficiency leads to lower iron-sulfur cluster-based complex activity in the mitochondria of cardiomyocytes, thereby, impairing mitochondrial respiration, ATP production, and contractility.5 HF patients with comorbid iron deficiency, consequently, are at an increased risk for hospitalizations, decreased quality of life, and exercise intolerance.

    Iron stores are regulated by serum hepcidin, an acute phase reactant. Inflammation from HF increases the production of hepcidin. Subsequently, hepcidin binds the ferroportin transporter, which is primarily responsible for gastrointestinal iron absorption and causes its lysosomal destruction.    Consequently, HF patients have a decreased ability to absorb oral iron.3 This was observed in the IRONOUT HF trial, in which clinically insignificant improvements in serum iron and TSAT conferred by oral iron supplementation over a 16-week period demonstrated no significant improvement in the change in peak VO2 (difference, 21 mL/min; 95% CI, -34 to 76; P-value, 0.46) or 6-minute walk distance (difference, -13 m; 95% CI, -24 to 23; P-value, 0.19) compared to patients receiving placebo.6

    To overcome the limitations of oral iron supplementation, many clinical trials have assessed the efficacy and safety of intravenous iron therapy to correct iron deficiency in HF. Intravenous iron supplementation may improve clinical outcomes in HF by increasing cardiac mitochondrial function.  

    Literature Review:
    Intravenous iron supplementation routinely improved functional capacity in randomized controlled trials of chronic HF patients. Study participants were generally characterized as New York Heart Association (NYHA) Class II-III with a left ventricular ejection fraction <45%, and all patients met criteria for iron deficiency (serum ferritin <100 mcg/L or 100-300 mcg/L with a TSAT <20%), regardless of concomitant anemia.7-10 In the FAIR-HF trial, intravenous ferric carboxymaltose improved self-reported patient global assessment and NYHA functional classification over 24 weeks of follow-up.7 Those results were replicated in the CONFIRM-HF trial in which intravenous ferric carboxymaltose improved patient’s 6-minute walk test (difference, 33 ± 11 meters; P=0.002), NYHA functional class, and Kansas City Cardiomyopathy Questionnaire scores when compared to placebo.8 Furthermore, the EFFECT-HF trial observed a significant improvement in peak VO with  intravenous ferric carboxymaltose use.9  Thus, the 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure states that it might be reasonable to utilize intravenous iron supplementation in NYHA class II and III HF patients to improve quality of life and functional status (Class IIb; Level of Evidence B-R).10  Recommendations for intravenous iron supplementation in acute HF, however, are absent from the guidelines.

    In a small prospective study, Reed et al. examined the safety and efficacy of intravenous sodium ferric gluconate 250 mg every 12 hours (total dose calculated by the Ganzoni formula, mean dose = 1,269 mg) in patients with NYHA class III-I HF and iron deficiency.  The study showed that intravenous sodium ferric gluconate increased the hemoglobin by 1.2 g/dL (95% CI, 0.45-1.9; P=0.005), ferritin by 364.2 ng/ml (95% CI, 129.7-598.7; P=0.007), and TSAT by 10.5% (95% CI, 6.5-14.6%; P<0.001).  Additionally, iron deficiency was no longer present in eight of the nine patients that followed up in the study.11  Kaminsky et al. further illustrated that patients with acute HF and anemia who received intravenous iron (mean dose = 1,057 mg) had greater improvement in hemoglobin in comparison to a no iron replacement (P=0.0001).12 The mean difference in hemoglobin from baseline for iron therapy was 0.74 g/dL on day 7 and 2.61 g/dL on day 28, whereas the control group only saw a mean difference of 0.01 g/dL and 0.23 g/dL on days 7 and 28, respectively.12  This study also found no statistical difference between iron therapy and the control group in respect to all-cause 30-day readmission rates (P=0.2787), but lack of statistical power precluded a definitive conclusion.12 In each study, intravenous iron was well-tolerated without significant adverse effects.11, 12

    Recently, the AFFIRM-AHF trial assessed the effect of intravenous ferric carboxymaltose on the risk of total HF hospitalizations and cardiovascular death in patients stabilized after acute HF. Patients included were hospitalized with acute HF with a left ventricular ejection fraction <50% and iron deficiency (serum ferritin <100 mcg/L or 100-300 mcg/L with a TSAT <20%).  Ferric carboxymaltose was administered as two repletion doses, up to 1,000 mg prior to discharge and six weeks later, based on patient weight and hemoglobin; subsequent doses were administered at 12 and 24 weeks if iron deficiency persisted upon follow-up. No significant difference in the composite endpoint of total HF hospitalizations and cardiovascular death between the intervention and placebo groups (RR, 0.79; 95% CI, 0.62-1.01; P=0.059). However, a pre-COVID-19 sensitivity analysis was performed and demonstrated a significant decrease in the composite primary outcome (RR, 0.75; 95% CI, 0.59-0.96; P=0.024). Ferric carboxymaltose also decreased in total hospitalizations (RR, 0.74; 95% CI, 0.58-0.94; P=0.013), days lost due to HF hospitalization and cardiovascular death (RR, 0.67; 95% CI, 0.47-0.97; P=0.035), and rate of first hospitalization due to HF or cardiovascular death (HR, 0.80; 95% CI, 0.66-0.98; P=0.030).  Conversely, the trial did not find a significant difference in cardiovascular death between the two groups (HR, 0.96; 95% CI, 0.70-1.32; P=0.81).13 Therefore, the trial provided evidence of reduced HF hospitalizations with the use of ferric carboxymaltose in stabilized acute HF patients.

    Intravenous iron supplementation is efficacious in patients with chronic or acute HF and iron deficiency by decreasing hospitalizations and improving exercise intolerance, NYHA functional classification, and quality of life. No major adverse events were observed by intravenous iron replacement. Patients admitted for acute HF should be screened for iron deficiency, and intravenous iron may be administered to decrease the risk of worsening HF symptoms and readmissions.


    1. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation. 2020;141(9):e139-e596.
    2.  Jackson SL, Tong X, King RJ, Loustalot F, Hong Y, Ritchey MD. National burden of heart failure events in the United States, 2006 to 2014. Circ Heart Fail. 2018;11(12):e004873.
    3. von Haehling S, Ebner N, Evertz R, Ponikowski P, Anker SD. Iron deficiency in heart failure: an overview. JACC Heart Fail. 2019;7(1):36-46.
    4. Cohen-Solal A, Damy T, Terbah M, et al. High prevalence of iron deficiency in patients with acute decompensated heart failure. Eur J Heart Fail. 2014;16:984-991.
    5. Hoes MF, Grote Beverborg N, Kijlstra JD, et al. Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function. Eur J Heart Fail. 2018;20(5):910-919.
    6. Lewis GD, Malhotra R, Hernandez AF, et al. Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: the IRONOUT HF randomized clinical trial. JAMA. 2017;317(19):1958-1966.
    7. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436-2448.
    8. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency†. Eur Heart J. 2015;36(11):657-668.
    9. van Veldhuisen DJ, Ponikowski P, van der Meer P, et al. Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency. Circulation. 2017;136(15):1374-1383.
    10. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e161.
    11. Reed BN, Blair EA, Thudium EM, et al. Effects of an accelerated intravenous iron regimen in hospitalized patients with advanced heart failure and iron deficiency. Pharmacotherapy. 2015;35(1):64-71.
    12. Kaminsky BM, Pogue KT, Hanigan S, Koelling TM, Dorsch MP. Effects of total dose infusion of iron intravenously in patients with acute heart failure and anemia (hemoglobin < 13 g/dl). Am J Cardiol. 2016;117(12):1942-1946.
    13. Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020;396(10266):1895-1904.
  • 03 Aug 2021 11:36 AM | Anonymous

    By: Veeraya White, PharmD Candidate 2022 – University of Health Sciences and Pharmacy in St. Louis

    Mentor: Brooke E. Gengler, PharmD, BCCP; Pharmacy Clinical Specialist, Cardiology, SSM Health Saint Louis University Hospital

    Coronavirus disease 2019 (COVID-19) is a viral respiratory infection caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) which has become a significant threat worldwide. The infection triggers host defense systems resulting in activation of coagulation and thrombin generation, called thromboinflammation.1 As a result, some patients with COVID-19 encounter complications associated with cytokine overproduction, hypercoagulability, and thrombosis. Thromboinflammation may lead to a life-threatening condition, disseminated intravascular coagulopathy (DIC), a condition in which blood clots throughout the body use up available clotting factors thereby increasing the risk of bleeding.2,3 Anticoagulants (ACs), such as low molecular weight heparin (LMWH), and unfractionated heparin (UFH), are used to prevent thrombosis.2 This article will discuss the appropriate criteria for anticoagulant venous thromboembolism (VTE) prophylaxis in patients with COVID-19. 

    Literature Review
    Early in the pandemic, clinicians identified that DIC was commonly associated with severe cases of COVID-19 that resulted in death.4 Upon closer examination, many of these patients experienced microvascular thrombosis or venous thromboembolism.5 As a result, several studies attempted to find an association between various biomarkers such as D-dimer and risk of thrombosis. One retrospective study from Wuhan, China found that patients with sepsis-induced coagulopathy scores (SIC) ≥4 or elevated D-dimers who were given prophylactic doses of LMWH had reduced mortality compared to those without.6

    Larger, prospective, randomized controlled trials have explored whether prophylactic anticoagulation is enough to prevent thrombosis or if intermediate intensity, doses between prophylactic and therapeutic anticoagulation, should be used instead. The ACTION study evaluated extended duration therapeutic anticoagulation with rivaroxaban or enoxaparin during admission followed by rivaroxaban for 30 days after discharge in acutely ill COVID-19 patients. Compared to standard VTE prophylaxis, therapeutic anticoagulation increased the risk of bleeding without improving clinical outcomes.7 In critically ill patients, receipt of early therapeutic anticoagulation within two days of admission was not associated with reduced mortality.8 Preliminary data from the multi-platform randomized controlled trial (mpRCT) also indicate that therapeutic anticoagulation did not improve survival or days free from organ support compared to standard pharmacologic prophylaxis. This trial was stopped early due to futility.9 Based on currently available evidence, most COVID-19 patients admitted to the hospital should be initiated on standard VTE prophylaxis rather than an intensified regimen.

    Application in Practice

    Thrombosis prophylaxis in hospitalized COVID-19 patients

    • Routine thromboprophylaxis should be used in all hospitalized non-pregnant patients with a standard dose of LMWH or UFH after careful assessment of bleeding risk. LMWH is the preferred agent due to lower frequency of administration.11,16,17
    • VTE prophylaxis regimens should be modified based on body weight, severe thrombocytopenia (i.e. platelet counts <25,000/µL in non-bleeding patients or 50,000/µL in bleeding patients), or declining renal function.10,13
    • In patients with a contraindication to pharmacologic prophylaxis, consistent application of intermittent pneumatic compression devices should be used with regular assessment.17
    • In critically ill patients, thromboprophylaxis should be initiated at standard doses. An intermediate dose may be considered in patients at high risk of thrombosis.17

    Recommended standard prophylaxis doses of anticoagulants (dose adjustments for renal function and obesity not included)10,12,13

    • Enoxaparin 40 mg subcutaneously (SUBQ) daily
    • Heparin 5000 units SUBQ every 8 hours (preferred in patients with creatinine clearance (CrCl) <15 mL/min or dialysis)

    Recommended intermediate doses of anticoagulants17

    • Enoxaparin 0.5 mg/kg SUBQ twice daily
    • Heparin 7500 units SUBQ every 8 hours

    Duration of VTE prophylaxis after hospital discharge10

    • Post-hospital VTE prophylaxis may be considered on a case-by-case basis for patients with COVID-19 who are low bleeding risk (e.g. IMPROVE bleed score <7.0) and:
      • Were admitted to the ICU, intubated, sedated, and possibly paralyzed for multiple days
      • Have ongoing VTE risk factors at the discharge (e.g. limited mobility, profound weakness, or not at baseline physical status)


    1. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033-2040.
    2. Moonla C, Sosothikul D, Chiasakul T, Rojnuckarin P, Uaprasert N. Anticoagulation and in-hospital mortality from coronavirus disease 2019: a systematic review and meta-analysis. Clin Appl Thromb Hemost. 2021; 27:10760296211008999.
    3. National Heart Lung and Blood Institute. Disseminated intravascular coagulation. Published October 2019. Accessed June 21, 2021.
    4. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18:844-847.
    5. McFadyen JD, Stevens H, Peter K. The emerging threat of (micro)thrombosis in COVID-19 and its therapeutic implications. Circulation Research. 2020;127:571-587.
    6. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099.
    7. Lopes RD, de Barros E Silva PGM, Furtado RHM, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet. 2021;397(10291):2253-2263.
    8. Al-Samkari H, Gupta S, Leaf RK, et al. Thrombosis, bleeding, and the observational effect of early therapeutic anticoagulation on survival in critically ill patients with COVID-19 [published correction appears in Ann Intern Med. 2021 Jun;174(6):888]. Ann Intern Med. 2021;174(5):622-632.
    9. Zarychanski R. The REMAP-CAP, ACTIV-4a, ATTACC investigators. Therapeutic anticoagulation in critically ill patients with COVID-19 – preliminary report.
    10. Benge C, DeWitt K. Anticoagulation Forum. Anticoagulation in COVID-19: summary of societal guidance. Updated December 2020. Accessed June 21, 2021.
    11. National Institutes of Health. Antithrombotic therapy in patients with COVID-19. Published February 2021. Accessed June 21, 2021.
    12. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(23):2950-2973.
    13. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-1026.
    14. Moores LK, Tritschler T, Brosnahan S, et al. Prevention, diagnosis, and treatment of VTE in patients With Coronavirus disease 2019: CHEST guideline and expert panel report. Chest. 2020;158(3):1143-1163.
    15. Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Adv. 2021;5(3):872-888.
    16. Spyropoulos AC, Levy JH, Ageno W, et al. Scientific and standardization committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020;18(8):1859-1865.
    17. Barnes GD, Burnett A, Allen A, et al. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis. 2020;50(1):72-81.
  • 03 Aug 2021 11:21 AM | Anonymous

    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:

    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.

    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.

    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.


    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
  • 03 Aug 2021 11:07 AM | Anonymous

    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
    Take CE Quiz

    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

    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

    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

    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

    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.

    Take CE Quiz


    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.
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    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.
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    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.
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    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.
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    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.
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    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.
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    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.
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    32. Greenway FL, Aronne LJ, Raben A, et al. A randomized, doubleblind, placebocontrolled 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.
  • 03 Aug 2021 10:42 AM | Anonymous

    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.
    Take CE Quiz

    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.

    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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    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

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