UMKC’s SSHP chapter had a challenging but strong spring semester. In February, KCHP and KU School of Pharmacy invited us to join their Pharmacy Forecast Workshop. Students learned about emerging healthcare trends and future opportunities of pharmacy practice. Groups discussed and came up with possible solutions to current practice problems involving electronic health records, Big Data, and payment reform. We had 80 members of the UMKC SSHP chapter attend this wonderful collaborative event.
This year in Springfield, SSHP members participated in various outreach initiatives including organizing an organ donor drive for students at Missouri State University and a legislative outreach campaign during COVID-19. Springfield’s Project Committee member Brandon Cole created materials explaining how to register for organ donation online. Springfield student members Zach Hitchcock and Amelia Godfrey organized a legislative calling campaign in partnership with APhA-ASP which included an informational session about the joint report released in March and ways students can contact their legislators. Next year, incoming Springfield Liaison Mariah Berg plans to focus on expanding community outreach by increasing member involvement with the Project Committee and finding new events/programs to teach the community about initiatives like Vial of Life.
Columbia's SSHP membership saw tremendous growth in participation over the past school year. Our members were excited about the opportunities to learn and lead in health systems pharmacy. We had a record level of involvement from students at events including general meetings, Residency Roundtable, and Pharmacy Forecast. Residency Roundtable was a highlight for the Columbia campus this year. We had 17 students in attendance as well as 6 residency program directors and residents.
We held our monthly general meetings throughout the semester with visiting speakers who shared their experiences working as health-system pharmacists. One noteworthy speaker we had was Gina Luchan, who was previously the 2018-2019 Executive Fellow in Association Leadership and Management. Luchan now serves as the Director of Academic Programs at ASHP. She presented on Practice Advancement Initiative (PAI) and empowered our students to play a role in improving patient outcomes in acute and ambulatory care settings. As pharmacy students, we want to help our current and future patients achieve optimal health outcomes by ensuring safe and effective medication use. One way we can do this is by learning about practice advancement opportunities during our time in pharmacy school. For many of the attendees, this was their first time hearing of PAI and enjoyed learning how they could make a difference.
During the week of final exams, our SSHP chapter talked to our students about maintaining their well-being and resilience through the power of social media. SSHP used Facebook to reach out to pharmacy students to promote ASHP’s initiative to encourage pharmacy resiliency. Topics included positive thinking, setting goals, and creatively solving problems among others.
The executive team is gearing up for our main events in the fall. Residency program directors should be on the lookout for their invitation to attend Residency Roundtable. The events will take place at each of the following UKMC campuses: Kansas City, Columbia, and Springfield. Our clinical skills competition and membership drive are planned for the fall as well. We acknowledge that conditions outside of our control may affect our ability to hold any or all of these events. We will notify all appropriate parties of any schedule changes.
We understand that this has been a challenging year. We are thankful for your involvement with SSHP and hope you’re staying safe and healthy! All three campuses are excited to jump into the new school year in August and see our chapter grow, serve, and learn.
St. Louis College of Pharmacy
By: Lauren Busch, STLCOP SSHP President and Maram Hamdan, STLCOP SSHP President-Elect; PharmD Candidates 2022
The St. Louis College of Pharmacy SSHP had a successful 2019-2020 school year despite the challenges presented by COVID-19 in the spring semester. The STLCOP SSHP held several residency preparation events including: the Introduction to Residency and CV 101 seminars led by faculty member Dr. Jack Burke; the Resident Roundtable with residents from all over the St. Louis area; and the Residency-Focused Mentorship Program events which continued to be expanded. The Residency-Focused Mentorship Program, which is a mentorship program between pre-professional students and students early in the pharmacy program (P1’s) and students later in the program (P2’s and P3’s), received the SSHP Outstanding Professional Development Project Award and was presented at the 2019 Midyear Clinical Meeting Student Society Showcase.
STLCOP SSHP worked with other student organizations on volunteering events including BooFest with JDRF and the other student organizations on campus, the Washington University Health Fair with STLCOP APhA-ASP, National Kidney Foundation kidney screenings with SNPhA, and tie blanket making events for local cancer patients hosted by SSHP. On Halloween, STLCOP SSHP held a Poison Control Lunch and Learn led by the SSM Health Director of Poison Control, Dr. Julie Weber, and students learned about the possibility of a rotation at the Missouri Poison Control Center and a career in this field.
The STLCOP SSHP held Practice Advancement Initiative (PAI) Week the week of February 24th and held several events during this week, including an APPE Student Panel during which P4 students explained how activities they completed during their rotations relate to the PAI pillars. Students were able to ask the P4s questions about rotations, applying for residencies, and tips for the future.
The Innovation and Development Committee introduced a new seminar, Combating Burnout in Healthcare Professionals Seminar, led by guest speaker Vicki Good, who shared her research on burnout and taught students about the prevalence of burnout for pharmacists and other healthcare professionals.
Although several events, including the Residency Director’s Roundtable, were cancelled due to COVID-19, STLCOP SSHP was able to hold a virtual CV review session for students with the help of STLCOP faculty and local StLSHP members. STLCOP SSHP is eager to host events for students once again in the fall.
By: Jack Pluenneke, PharmD Candidate 2021 and Andrew Smith, Pharm.D., FCCP, BCCP, BCPS; UMKC School of Pharmacy
There has been a large amount of observational evidence supporting low-density lipoprotein cholesterol (LDL-C) as a causal risk factor for the development of atherosclerotic cardiovascular disease (ASCVD).1 With the emergence of genetic and clinical trials showing linear relationships between exposure to cholesterol, in particular LDL-C, and ASCVD risks, reducing LDL-C levels has become a standard in the prevention of cardiovascular disease.2,3,4 Lifestyle modification continues to be one of the most important and effective interventions in the management of high LDL-C levels.5 Unfortunately, many patients require additional LDL-C lowering despite lifestyle modification and must turn to pharmacological management. HMG CoA reductase inhibitors (statins) are the most established and cost effective first line medication for the treatment of elevated LDL-C levels.6 Statins are generally well tolerated, but their use can be limited by their adverse reactions. Statin- associated muscle symptoms are the most frequent adverse reaction leading to nonadherence or discontinuation.7 Other pharmacological therapies have been developed to help patients who are unable to tolerate statin therapy, such as ezetimibe and PSCK9 inhibitors. Although these agents are also generally well tolerated, they do have disadvantages. Ezetimibe only has modest LDL-C lowering effects and PSCK9 inhibitors are limited by their current costs and route of use.4 Due to these limitations, many patients fail to achieve goal LDL-C levels and continue to be at risk for ASCVD events.8
In February 2020, the U.S Food and Drug Administration (FDA) approved a first in its class medication for patients with heterozygous familial hypercholesterolemia or established ASCVD who require additional lowering of LDL-C.9 Bempedoic acid, sold under the brand name Nexletol™, reduces LDL-C by inhibiting adenosine triphosphate-citrate lyase (ACL).10 ACL acts upstream of HMG-CoA reductase (statins site of action) and catalyzes the production of acetyl coenzyme A. Acetyl coenzyme A is the precursor of the mevalonate pathway of cholesterol synthesis.10 Similar to statins, bempedoic acid leads to upregulation of LDL receptors and increased uptake of LDL particles, thereby reducing LDL-C levels.10 Bempedoic acid is converted to its active form by a hepatic synthetase that is not expressed in skeletal muscle, resulting in fewer effects on the musculoskeletal system.10 Due to the potential decreased muscle adverse effects of bempedoic acid, this medication may be useful in patients who require additional LDL-C lowering, despite being on maximum tolerated statin therapy, or those with statin intolerance. This remainder of this article will evaluate the phase 3 trials resulting in bempedoic acid’s approval, analyze the safety and efficacy of this drug, and provide important information on its clinical use.
Cholesterol Lowering via Bempedoic acid, an ACL-inhibiting Regimen (CLEAR) Trials
The CLEAR Harmony trial was a double-blind, placebo-controlled, randomized control trial (RCT) that primarily evaluated the safety of bempedoic acid 180mg daily in patients with heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease, or both.11 To be included in the study, patients had to have an LDL-C ≥70 mg/dL and be on maximally tolerated statin therapy. Safety parameters between bempedoic acid vs placebo were determined by incidence of adverse events and changes in safety lab values. The incidence of severe adverse events did not differ between the two groups (14.5% vs. 14.0%; P=0.80). However, the incidence of adverse events leading to a discontinuation of bempedoic acid was different (10.9% vs. 7.1%; P<0.005). In addition, the incidence of gout was higher in the bempedoic acid group versus placebo (1.2% vs. 0.3%; P<0.03). Efficacy of bempedoic acid versus placebo was evaluated as a secondary outcome measure. A difference of -18.1% LDL-C lowering was seen in the patients treated with bempedoic acid compared to placebo at week 12 (95% confidence interval [CI] -20.0% to -16.1%; P<0.001). The CLEAR Harmony trial suggests that bempedoic acid added to maximally tolerated statin therapy is generally well tolerated and led to lower overall LDL cholesterol levels.
The CLEAR Serenity trial was a double-blind, placebo controlled, RCT that analyzed the efficacy and safety of bempedoic acid 180mg daily in patients with hypercholesterolemia and a history of intolerance to at least 2 statins.12 Patients were eligible if their LDL-C levels were ≥130 mg/dL, for primary prevention, and ≥100 mg/dL for those requiring secondary prevention. The primary outcome measure was the mean percent change in LDL-C from baseline at week 12. A difference of -21.4% reduction in LDL-C levels was seen at week 12 in patients treated with bempedoic acid when compared to placebo (95% CI -25.1 to -17.7%; P<0.001). The overall incidence of adverse reactions was similar between the groups with, with the most common treatment-emergent adverse event being muscle related. Of the muscle related adverse effects, myalgia occurred in 4.7% in patients on bempedoic acid and 7.2% of patients in the placebo group. Patients on bempedoic acid did report more adverse reactions resulting in discontinuation (18.4% vs. 11.7%), there was no mention of statistically significance between the groups. The CLEAR Serenity trial suggests that bempedoic acid is an effective option for lipid lowering and is generally well tolerated in in patients who cannot tolerate statin therapy.
The CLEAR Tranquility trial was a double-blind, placebo-controlled, RCT that investigated the efficacy and safety of bempedoic acid 180mg daily in statin-intolerant patients taking ezetimibe.13 This study enrolled patients with a history of statin intolerance and an LDL-C ≥100 mg/dL while on ezetimibe. The primary outcome measure was the percent change in LDL-C at week 12 compared to baseline. A 28.5% reduction was seen in patients taking ezetimibe with the addition of bempedoic acid as compared to the addition of placebo at week 12 (bempedoic acid -23.5% vs. +5.0% placebo; P<0.001).13 In regards of safety, rates of treatment-emergent adverse events, muscle- related adverse events, discontinuation were similar between groups. The CLEAR Tranquility trial suggests that bempedoic acid, when combined with ezetimibe, is safe and effective for patients who require additional LDL-C lowering and are intolerant to statins.
Lastly, the CLEAR Wisdom trial was a double-blind, placebo-controlled, RCT that analyzed the efficacy and safety of bempedoic acid vs placebo in patients at high risk for cardiovascular disease when added to maximally tolerated lipid-lowering therapy.14 The trial included patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both and a LDL-C ≥70 mg/dL while taking a maximally tolerated statin or other lipid-lowering therapy. The primary outcome measure was the percent change in LDL-C at week 12 as compared to baseline. A placebo-corrected difference of -17.4% was seen at week 12 in patients treated with bempedoic acid in addition to their maximally tolerated LDL-C lowering therapy regimen when compared to placebo (95% CI -19.5 to -10.0%; P<0.001). Adverse events between the bempedoic acid group and placebo group were similar. The most common included urinary tract infections (5.0% vs. 1.9%) and hyperuricemia (4.2% and 1.9%), respectively. The CLEAR Wisdom trial suggests that in patients at high risk for cardiovascular disease receiving maximally tolerated statins requiring additional LDL-C lowering, bempedoic acid was safe and effective in further lowering of LDL-C levels.
Clinical Utility of Bempedoic Acid
Bempedoic acid is currently available as a 180mg oral tablet (with or without ezetimibe) and dosed once daily with or without food.15,16 No dosage adjustments are required for patients with mild to moderate hepatic impairment as indicated by Child-Pugh Class A or B, or who have an estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2.16 Patients with severe hepatic impairment, indicated by Child-Pugh Class C, or those with an eGFR of <30 ml/min/1.73 m2 have not been studied. Currently, there are no identified contraindications according to the manufacturer.15 Warnings and/or precautions include hyperuricemia and tendon rupture.16 According to the manufacturer, increase in uric acid levels usually occur within the first 2 weeks of treatment initiation and persisted throughout treatment.15 It is recommended that health care providers monitor patients for signs and symptoms of hyperuricemia and gout, as well as monitor serum uric acid concentrations when clinically indicated.16 Tendon rupture has been reported within weeks to months of initiation. Health care providers should consider alternate therapy in patients with previous tendon disorders or tendon ruptures, or in patients at high risk for tendon rupture.16 Based on the mechanism of action of bempedoic acid, in utero exposure may cause fetal harm and should be discontinued if pregnancy occurs.16 According to the drug manufacturer, Esperion, bempedoic acid will cost $10 a day, or for patients who qualify, $10 for a 3 month supply.17
Based on the results of the CLEAR trials, bempedoic acid is effective for patients that require additional LDL-C lowering, or who have a history of statin intolerance. There is a risk that patients may develop an adverse reaction requiring discontinuation, so they should be monitored closely. The approval of bempedoic acid, a non-statin agent, will provide healthcare providers with more flexibility in the treatment of hypercholesterolemia and ASCVD. An important limitation to note is that long term safety, durability, and clinical effect of bempedoic acid has not been established. Further research is needed to establish the effect of bempedoic acid on clinical outcomes such as the rates of nonfatal myocardial infarction, stroke and cardiovascular death.
By: Ashley Jose, PharmD Candidate Class of 2021; St. Louis College of Pharmacy
Mentor: Emily Walsh, PharmD; Adult Multispecialty Clinics and University of Iowa Hospitals and Clinics
Venous thromboembolism (VTE) is the second most common cause of mortality in patients with cancer and the most frequent complication of malignancy.1 The estimated annual incidence of VTE among the general population is 1 to 2 per 1,000 people.1 In patients with cancer-associated thrombosis (CAT), the estimated risk of VTE is four to six times higher, and overall survival rates are much lower with significantly worse prognosis1. This increased risk of VTE is often multifactorial and can be caused by numerous patient and cancer-related factors, such as immobility, site and severity of cancer, stage and histology of the tumor, and treatment.1,2 Patients with CAT are also at a heightened risk of bleeding due to malignancy and anticoagulation. The economic burden of CAT is very high, with health care costs 40-50% higher than patients without CAT.1
Until recently, the standard of care for the treatment of CAT according to multiple practice guidelines has been low molecular weight heparin (LMWH), which was found to reduce VTE recurrence in cancer patients in various studies. The CLOT trial compared the efficacy of LMWH to oral vitamin K antagonist (VKA) treatment in preventing recurrence of thrombosis in patients with cancer.3 Patients were randomized to receive weight-based dalteparin or warfarin with an INR goal of 2-3 for 6 months. Dalteparin was found to significantly reduce the risk of recurrent VTE without increasing the risk of bleeding. LMWHs have a fast onset of action, reach steady state quickly, and avoid the need for oral absorption, which is especially useful for patients with poor oral intake. However, LMWH may cause adherence issues due to subcutaneous route of administration.
Direct oral anticoagulants (DOACs) have become the standard of care for the treatment of VTE in non-cancer patients based on efficacy and safety observed in landmark clinical trials. DOACs are a favorable treatment option for VTE as they do not require laboratory monitoring and have fewer drug-drug interactions than oral VKA's. However, landmark trials assessing the efficacy of DOACs for the treatment of VTE in the general population had a low enrollment of cancer patients, thus requiring further investigation of the use of these agents for the treatment of CAT. Recent clinical trials have been conducted to attempt to determine the place in therapy for DOACs for the treatment of CAT.
Clinical Trial Review
The SELECT-D trial was a multicenter, randomized, open-label, pilot trial that assessed the efficacy and safety of rivaroxaban for treatment of CAT.4 Patients with active VTE were randomized to rivaroxaban 15 mg twice daily for 3 weeks, then 20 mg once daily or dalteparin 200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6 for a total of 6 months. The most prevalent cancers were colorectal, lung, and breast cancer. The cumulative rate of recurrent VTE was 4% for patients in the rivaroxaban group compared to 11% in the dalteparin group (HR, 0.43; 95% CI, 0.19 to 0.99). The primary safety endpoint of major bleeding occurred in 11 patients receiving rivaroxaban and 6 patients receiving dalteparin, with a cumulative major bleed rate at 6 months of 6% and 4%, respectively, (HR, 1.83; 95% CI, 0.68 to 4.96). More major bleeding occurred in patients receiving rivaroxaban, especially patients with gastrointestinal or esophageal cancer. Significantly more clinically relevant non-major bleeding (CRNMB) occurred in patients receiving rivaroxaban compared to dalteparin (13 vs 4%, HR 3.76, 95% CI 1.63 to 8.69). This trial provided evidence that patients receiving rivaroxaban had significantly fewer episodes of recurrent VTE at the expense of increased bleeding, especially in patients with esophageal cancer.
HOKUSAI-VTE trial was an open-label, non-inferiority trial that assessed the efficacy and safety of edoxaban in patients with VTE and cancer.5 Patients were randomized to receive either edoxaban 60 mg daily or subcutaneous dalteparin 200 IU/kg once daily for 30 days, then 150 UI/kg once daily and followed for 12 months. The primary composite outcome of recurrent VTE or major bleed occurred in 67 patients (12.8%) receiving edoxaban compared to 71 patients (13.5%) receiving dalteparin (HR, 0.97; 95% CI 0.70 to 1.36; P=0.006 for non-inferiority, 0.87 for superiority). There was no difference between edoxaban and dalteparin in regards to recurrent VTE (7.9 vs 11.3%, p = 0.09), but there was significantly more major bleeding (6.9 vs 4%, p = 0.04), especially gastrointestinal bleeding in the setting of gastrointestinal cancer. This trial provided evidence that edoxaban is non-inferior to treatment with dalteparin for the composite outcome of recurrent VTE or major bleeding for up to 12 months. Similar to the SELECT- D trial, patients in the edoxaban group were found to have higher rates of major bleeding, especially bleeds that were gastrointestinal in nature and occurring in patients with gastrointestinal malignancy
The Caravaggio trial was a multinational, randomized, open-label, non-inferiority trial aimed to assess the safety and efficacy of apixaban in patients with CAT.6 Patients with active VTE were randomized to apixaban 10 mg twice daily for seven days, followed by 5 mg twice daily or dalteparin 200 units/kg once daily for one month, followed by 150 units/kg once daily for a total of 6 months. This trial mainly included advanced active cancers and had the highest amount of patients with ECOG performance status score of 1. The most common cancer types included were gastrointestinal, colorectal, and lung cancer. The primary outcome of recurrent VTE occurred in 32 patients (5.6%) in the apixaban group vs 46 patients (7.9%) in the dalteparin group (HR, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for non-inferiority; P=0.09 for superiority). The primary safety outcome of major bleeding occurred in 22 patients (3.8%) receiving apixaban compared to 23 patients (4%) receiving dalteparin (p = 0.60). The authors of the Caravaggio trial concluded that apixaban is non-inferior to subcutaneous dalteparin for preventing recurrent VTE in cancer patients with no difference in bleeding. This trial uniquely had less frequency of major and gastrointestinal major gastrointestinal bleeding compared to Hokusai-VTE and SELECT-D.
Takeaways and Recommendations
Based on the results of recently published clinical trials discussed above, DOACs appear to be efficacious in the treatment of CAT. However, rivaroxaban and edoxaban appear to have an increased risk of bleeding, especially those that are gastrointestinal in nature in those with gastrointestinal cancer.4-5 Some clinical practice guidelines for the treatment of cancer associated thrombosis have been updated based on the results of these trials. The CHEST guidelines, last updated in 2016, recommend LMWH over oral VKAs or any DOACs for the treatment of CAT.7 The 2020 ASCO guidelines were recently updated and recommend use of LMWH, edoxaban, or rivaroxaban for the treatment of CAT.8 NCCN 2020 guidelines recommend the use of DOACs, particularly apixaban, rivaroxaban and edoxaban, but suggest using LMWH in patients with CAT with gastric or gastroesophageal lesions.8-9 Both NCCN and CHEST guidelines recommend at least 3 months of treatment or as long as active cancer or cancer therapy.7,9
There are questions that remain regarding the use of DOACs for treatment of CAT. Currently, no head to head clinical trials are available to assess which DOAC is superior in the treatment of CAT. The duration of anticoagulation differed between all three trials, ranging from six to twelve months, which limits our ability to determine long term safety and efficacy. Cohort studies have found that the risk of recurrent VTE in CAT can run beyond 6 months, therefore a duration longer than 6 months may be beneficial after weighing the risk of recurrent VTE versus risk of bleed.10 More information is also needed pertaining to efficacy and safety of treatment across cancer type and severity, as the patient populations in these studies were diverse.
Patient preference, cancer specific factors, and patient specific factors should be utilized to select an appropriate anticoagulant for the treatment of CAT. DOACs appear to have a place in therapy for CAT and are conveniently dosed and administered. However, DOACs can be more costly, have a limited place in therapy in those with renal insufficiency and should be used very cautiously in those at increased risk of bleeding or in those with GI malignancy.10 LMWH can still be considered as a viable alternative, especially in those with cost concerns, concerns related to GI absorption, or difficulty with oral intake.
By: Meredith Vigneaux, PharmD; Mercy Hospital Springfield
The number one cause of death for patients with diabetes is due to cardiovascular (CV) disease, therefore lowering hemoglobin A1c with a medication that does not increase CV disease risk has become a central focus of diabetes treatment. Metformin was the first glucose lowering drug to demonstrate a positive effect on CV risk in the United Kingdom Prospective Diabetes Study (UKPDS), which ended in 1997.1,2 Since the correlation between the use of rosiglitazone3,4,5 and an increase in cardiovascular (CV) risk, specifically increased occurrence of heart failure (HF) hospitalizations, the FDA has recommended that new diabetes medications “demonstrate that the therapy will not result in an unacceptable increase in CV risk”.6 These trials are referred to as the Cardiovascular Outcomes Trials (CVOT). From 2008 to 2019 the FDA has required CVOT to be completed on new antihyperglycemic medications. They are currently reviewing the need for CVOT and are proposing adjusting this requirement in the near future.7
Cardiovascular Outcome Trials by Class
CVOT are designed to initially evaluate cardiovascular harm. If the medication shows no harm compared to placebo, when added to standard of care, the medication can then be evaluated for cardiovascular benefit if the study is powered for superiority. The three-part major adverse cardiovascular events (MACE) is composed of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke and is frequently the primary endpoint for CVOT. A four-part MACE endpoint has been used in some CVOT and adds hospitalization for unstable angina as the fourth part of the composite. Results from several CVOT trials are summarized in Table 1 and trials with significant outcomes are presented in more detail.
Dipeptidyl Peptidase-4 Inhibitors (DPP4)
Dipeptidyl peptidase-4 inhibitors work by inhibiting dipeptidyl peptidase (DPP4), therefore prolonging incretin levels, which helps regulate glucose homeostasis by increasing insulin synthesis and insulin release from beta cells. They also work by decreasing glucagon secretion from alpha cells. Cardiovascular benefit has not been demonstrated with DDP4 agents and possible HF risk has not shown to be a class effect.
The Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care (EXAMINE) trial, evaluating a three-part MACE in 5,380 patients with Type 2 Diabetes Mellitus (T2DM) and preexisting CV disease. 17 There was a 0.5% difference in MACE with alogliptin treatment compared to placebo. No statistically significant difference was seen in the alogliptin versus placebo for the primary endpoint, therefore no cardiovascular benefit was observed. There was an increase in hospitalization from heart failure in the alogliptin group that was statistically significant with a 0.6% difference in heart failure hospitalizations between the treatment group and placebo. Of further interest, there was a 0.3% difference in patients who had a history of heart failure and a 0.9% difference in patients who had no history of hospitalizations due to heart failure.33
In the Saxagliptin Assessment of Vascular Outcomes in Patients with Diabetes Mellitus (SAVOR) Thrombolysis in Myocardial Infarction (TIMI) 53 trial, the primary outcome was three-part MACE in 16,492 participants. 18 Patients had T2DM with multiple risk factors for CV disease or a history of CV disease. Saxagliptin was compared to placebo and there was a 0.1% difference in MACE, which was not statistically significant, therefore no cardiovascular benefit was observed. There was an observed increase in heart failure hospitalizations that was not statistically significant in the patients receiving saxagliptin (0.7% difference in heart failure hospitalizations between the two groups).
The primary outcome of a four-part MACE with sitagliptin was evaluated in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) trial, in 14,671 participants.19 Patients had T2DM with Acute Coronary Syndrome (ACS) within 15-90 days before randomization. There was a 0.2% difference in MACE with sitagliptin treatment compared to placebo. No statistically significant difference was seen in sitagliptin versus placebo for the primary endpoint; therefore, no cardiovascular benefit was observed. There was no statistically significant increase in heart failure hospitalization in the patients receiving sitagliptin (0.1% difference in heart failure hospitalizations between the two groups).
Glucagon-like peptide-1 (GLP-1)
Glucagon-like peptide-1 acts as an incretin-like hormone which increases glucose-dependent insulin secretion, decreases inappropriate glucagon secretion, increases beta cell growth and replication, decreases gastric emptying, and increases satiety. With GLP-1 agents, a cardiovascular benefit has not been demonstrated as a class effect, but three of these agents have proven cardiovascular benefit.
The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, the primary outcome was four-part MACE in 6,068 participants.20,21 Patients had T2DM and an acute coronary event within 180 days before screening. There was a 0.2% difference in MACE with lixisenatide treatment compared to placebo. No statistically significant difference was seen in lixisenatide versus placebo for the primary endpoint; therefore, no cardiovascular benefit was observed. Lixisenatide provided an average weight loss of 0.6 kg. Of note, there was a decrease in hospitalization from heart failure observed in the lixisenatide group (0.5% difference between lixisenatide and placebo). It is important to note that of the GLP-1 CVOTs, this is the trial with the highest risk study population as they had recently experienced a cardiac event.
In the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial, the primary outcome was three-part MACE in 14,752 participants.22 Patients had T2DM with or without preexisting CV disease. There was a 0.8% difference in MACE with exenatide treatment compared to placebo. No statistically significant difference was seen in exenatide versus placebo for the primary endpoint; therefore, no cardiovascular benefit was observed. Exenatide provided an average weight loss of 1.27kg.
In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, the primary outcome was three-part MACE in 9,340 participants.23,24 Patients had T2DM and kidney disease, HF, or CV disease and were greater than 50 years of age, or the patients had T2DM and had more than one CV risk factor and were greater than 60 years of age. There was a 1.9% difference in MACE with liraglutide treatment compared to placebo. Superiority was seen with liraglutide versus placebo, therefore cardiovascular benefit observed. Patients who were receiving liraglutide required less insulin. The superiority outcome was mainly driven by a decrease in death from cardiovascular cause and fatal or non-fatal myocardial infarction. Liraglutide provided an average weight loss of 5kg.
In the Peptide Innovation for Early Diabetes Treatment (PIONEER-6) trial, the primary outcome was three-part MACE in 3,176 participants.25 Patients had T2DM and Chronic Kidney Disease (CKD) or CV disease and were greater than 50 years of age, or the patients had T2DM and had more than one CV risk factor and were greater than 60 years of age. There was a 1% difference in MACE with oral semaglutide treatment compared to placebo. No statistically significant difference was seen in oral semaglutide versus placebo for the primary endpoint; therefore, no cardiovascular benefit was observed. Oral semaglutide provided an average A1c decrease of 1% and an average weight loss of 4.2kg. Semaglutide’s mechanism of action in an oral option may be a beneficial option in patients who require additional A1c lowering and post-prandial glucose coverage, who are not willing to do an injection, and do not have additional CV risk.
In the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial, the primary outcome was three-part MACE in 9,901 participants.26 Patients had T2DM and were at least age greater than 50 years with previous CV disease; or patients had T2DM and were at least age greater than 60 years with two cardiovascular risk factors. There was a 1.4% difference in MACE with dulaglutide treatment compared to placebo. There was superiority with dulaglutide over placebo; therefore, cardiovascular benefit was observed. The superiority outcome was mainly driven by a decrease in non-fatal and fatal stroke. Dulaglutide provided an average weight loss of 3 kg.
In the Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6) ,the primary outcome was three-part MACE in 3,297 participants.27 Patients had T2DM and CKD, HF, or CV disease and were greater than 50 years of age, or the patients had T2DM and had more than one CV risk factor and were greater than 60 years of age. There was a 2.3% difference in MACE with subcutaneous semaglutide treatment compared to placebo. Semaglutide was superior to placebo, therefore cardiovascular benefit was observed. The superiority outcome was mainly driven by a decrease in nonfatal stroke and revascularization. Patients who were receiving semaglutide lost an average of 4.2kg. This was the second once weekly GLP-1 approved with cardiovascular benefit. Semaglutide has been studied head to head with Trulicity and was found to have greater A1c lowering and weight loss.34
Sodium Glucose Transport-2 (SGLT-2) Inhibitors
The sodium glucose transport-2 (SGLT-2) inhibitors work by inhibiting SGLT-2 in the proximal renal tubule and reduces glucose reabsorption from the tubular lumen and ultimately reduces blood glucose concentrations. The cardiovascular benefit is considered a class effect of the SGLT-2 inhibitors; however the individual agents show variability in the type of cardiovascular benefit. While each of the SGLT-2 medications have renal dose adjustments, they are being studied in the CKD population for possible renal protection and utility in preventing renal death.
In the CANagliflozin cardioVascular Assessment Study (CANVAS) trial, the primary outcome was three-part MACE in 10,142 participants. 30 Patients had T2DM and preexisting CV disease who were greater than 30 years old or patients who had T2DM and were greater than 50 years old with more than two CV risk factors. Superiority was found with canagliflozin compared to placebo, therefore cardiovascular benefit was seen. Canagliflozin cardiovascular benefit was statistically significant for Atherosclerotic Cardiovascular Disease (ASCVD). While the primary outcome was found to be statistically significant, when evaluated as a subgroup analysis of death from cardiovascular cause, nonfatal myocardial infarction and nonfatal stroke, none of the groups had statistical significance. There is question regarding the validity of the primary outcome having statistical significance in the primary outcome because the subgroups did not have statistical significance. However, in a separate study, canagliflozin has been studied in CKD and was shown to be statistically significant in reducing renal or cardiovascular death.35
In the Dapagliflozin Effect on CardiovascuLAR Events (DECLARE) Thrombolysis In Myocardial Infarction (TIMI) 58 trial, the primary outcome was three-part MACE and composite of cardiovascular death or hospitalization for heart failure in 17,276 participants. 31 Patients had T2DM and were at least age of 40 years old and had established CV disease or risk factors for CV disease. There was a 0.6% difference in MACE with dapagliflozin treatment compared to placebo. The decreased rate in MACE was not statistically significant. There was a 0.9% difference in composite of cardiovascular death or hospitalization for heart failure for the treatment group, this outcome was shown to be statistically significant. Superiority with dapagliflozin compared to placebo, therefore cardiovascular benefit was seen. The superiority outcome was primarily driven by a decrease in hospitalizations from heart failure. Dapagliflozin cardiovascular benefit was statistically significant for HF. In a follow up study evaluating patients with New York Heart Association Class II, III, or IV heart failure with an ejection fraction of 40% or less receiving placebo or dapagliflozin, it was found that dapagliflozin group had a decreased risk of worsening heart failure.36 Dapagliflozin now has an FDA indication for reducing the risk of cardiovascular death for patients with heart failure with reduced ejection fraction or preserved ejection fraction.
In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG) trial, the primary outcome was three-part MACE in 7,020 participants.32 Patients had T2DM with preexisting CV disease and a Body Mass Index (BMI) less than 45 kg/m2 and eGFR greater than 30mL/min/1.73m2. There was a 1.5% difference in MACE in patients treated with empagliflozin compared to the placebo treatment group. Superiority with empagliflozin compared to placebo, therefore cardiovascular benefit was seen. Empagliflozin cardiovascular benefit was statistically significant for ASCVD and a decrease in hospitalizations from heart failure (HHF). A decrease in HHF was the driving outcome in the combined ASCVD and HF benefit outcome.
Current Guideline Recommendations
Metformin continues to be first line therapy per the American Diabetes Association (ADA)37 and the American Association of Clinical Endocrinologists (AACE)38 due to its robust CV safety data in comparison with sulfonylureas from the UKPDS trials. Along with the addition of lifestyle modifications with metformin, ADA recommends use of a GLP-1 or SGLT-2 with proven cardiovascular benefit and additional therapy to achieve goal A1c in patients who have established ASCVD. AACE also recommends addition of GLP-1 or SGLT-2 to metformin if coronary heart disease (CHD) is present. The American Heart Association (AHA)39 and the American College of Cardiology (ACC) recommend consideration of addition of cardiovascular protective SGLT-2 or GLP-1 to metformin in patients whose A1c is greater than 7% and have CV risk factors.
By: Kyle Stupca, PharmD; Mercy Hospital - Springfield
The incidence of atrial fibrillation (AF) in patients with acute coronary syndromes (ACS) ranges from 10% to 20% and increases with patient age and severity of myocardial infarction (MI). Subsequently, AF is associated with increased in-hospital mortality, 30-day mortality, and 1-year mortality.1 Stroke rates are higher in patients with MI and AF than those without AF with the incidence being 3.1% in patients with AF compared to 1.3% in patients without AF.2 Patients treated for ACS normally require dual antiplatelet therapy (DAPT) with aspirin (ASA) plus a platelet P2Y12 inhibitor such as clopidogrel, ticagrelor, or prasugrel. DAPT has been proven to reduce the incidence of recurrent ischemic events and stent thrombosis but is less effective in reducing the incidence of cardioembolic stroke associated with AF.3,4 As a result, patients with AF may require the addition of an anticoagulant such as warfarin or a direct oral anticoagulant (DOAC) for the primary prevention of stroke if they are at a high risk.5 The resulting regimen consists of DAPT with the addition of warfarin or a DOAC and is otherwise known as triple antithrombotic therapy. Although patients are at an increased risk of thrombosis as a result of AF, initiating triple antithrombotic therapy comes with its own set of risks, the most concerning of which is clinically significant bleeding. Because of this, it is important to fully evaluate the benefits and risks of these regimens before recommending them for our patients.
There have been numerous important trials in recent years evaluating the use of triple antithrombotic therapy compared to some form of double therapy with an anticoagulant and a single antiplatelet agent. Several of these trials were utilized when formulating current guideline recommendations for the management of patients with AF and ACS.
The use of clopidogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events in adult patients receiving oral anticoagulants (OAC) and undergoing percutaneous coronary intervention (PCI).
Six weeks of triple antithrombotic therapy, defined as clopidogrel, aspirin, and a DOAC, was not associated with improved net clinical outcomes compared to six months triple antithrombotic therapy. Both major bleeding risk and thrombotic risk appeared to be similar with both durations of triple therapy.
PIONEER AF PCI8
Patients who had AF and were undergoing stent placement experienced less bleeding at 1 year with low dose rivaroxaban plus single or dual antiplatelet therapy compared to warfarin plus dual antiplatelet therapy.
Patients with AF who had undergone PCI had a lower risk of bleeding when receiving dual therapy with dabigatran and a P2Y12 inhibitor than those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. The dual therapy regimen was found to be noninferior to triple therapy with regards to the risk of thromboembolic events.
In patients with AF and a recent ACS or PCI, an antithrombotic regimen with apixaban and a P2Y12 inhibitor without aspirin, resulted in less bleeding without significant difference in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both.
Prior to the most recent update to the 2014 AHA/ACC/HRS AF Guidelines in 2019, it was recommended that all patients with ACS and AF with a CHA2DS2-VASc score of 2 or greater receive anticoagulation with warfarin unless it is contraindicated.11 Although these older guidelines did discuss minimizing the duration of triple therapy and suggest the option of using oral anticoagulation plus clopidogrel with or without aspirin, there was minimal data to support a formal recommendation. However, more recent studies have shown an improved safety profile with DOACs and dual therapy regimens with regard to bleeding events and similar efficacy at preventing cardioembolic events compared to triple antithrombotic therapy. As a result, dual therapy with an oral anticoagulant and a P2Y12 inhibitor may be more appropriate in some of our patient populations that are at an increased risk of bleeding. The AHA/ACC/HRS AF Guidelines were updated in 2019 to reflect these new findings, and specific recommendations are listed below.
Application in Practice
The incidence of AF in patients with ACS is not uncommon and management often requires the use of both antiplatelet agents and anticoagulants. These medications are vital at reducing the risk of thromboembolic events but put our patients at risk of bleeding. As healthcare professionals, it is important to fully weigh the risks and benefits before initiating triple antithrombotic therapy and to advocate for less aggressive antithrombotic regimens when it is clinically indicated.
By: Brooke Lucas, PharmD and Kelsey Sachtleben, PharmD; PGY1 Pharmacy Residents
Mentor: Emily Buchanan, Pharm.D., BCPS, SSM Health St. Clare Hospital
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Calcium is one of the most abundant cations found in the human body and plays an important role in myocardial function, enzyme activity, neural transmission, coagulation, and other cellular functions. Most calcium is found in the bones with the remainder of calcium found in cells and extracellular fluid.1,2 Hypercalcemia affects approximately one to two percent of the general population, with most of these cases (90%) due to primary hyperparathyroidism and hypercalcemia of malignancy.3 Patients can often tolerate chronic hypercalcemia, but acute hypercalcemia can lead to more severe symptoms and up to a 50% mortality rate for patients with untreated hypercalcemia of malignancy.4
The skeletal tissue of the human body not only provides necessary structural support, but acts as a reservoir from which calcium can be exchanged. Approximately 99% of the total body calcium stores are contained within skeletal tissues. Although only a small fraction of total body calcium exists in extracellular and intracellular fluid, such calcium concentrations are essential for normal action potential propagation, muscle contraction, endocrine and exocrine secretion processes, activation of coagulation factors, and more. Calcium homeostasis is controlled by a set of endocrine regulatory factors discussed further below.5
The three key regulators of ionized calcium concentrations throughout the body are parathyroid hormone (PTH), 1,25-dihydroxy vitamin D3 (calcitriol), and calcitonin. PTH is important in calcium homeostasis as part of hormone signaling and negative feedback loops. When low levels of extracellular calcium are detected, the parathyroid glands begin secreting PTH. PTH works to increase serum calcium by stimulating the release of calcium from skeletal tissue, increasing reabsorption of calcium in the renal tubules, and increasing the absorption of calcium from the gastrointestinal tract with the help of calcitriol released by the kidneys.5 PTH also stimulates phosphate excretion in the kidneys, so low serum phosphate levels may be seen in patients with hypercalcemia secondary to hyperparathyroidism.
Vitamin D is a steroid hormone that is obtained through both diet and activation of vitamin D precursors on the skin via interaction with sunlight. The active form of vitamin D in the body is 1,25-dihydroxy vitamin D3, also known as calcitriol, which is produced by a hydroxylation process in the renal tubules. In the setting of increased serum calcium levels or ingestion of calcium-rich foods, calcitriol is produced in the kidneys and released into circulation. Aside from directly increasing calcium absorption in the gastrointestinal tract, calcitriol also promotes bone resorption, decreases renal excretion of calcium, and stimulates absorption of phosphate from the gastrointestinal tract, thus leading to elevated phosphate levels in patients with calcitriol mediated hypercalcemia.
When serum calcium levels begin to rise above the normal threshold, the hormone calcitonin begins to play a role in maintaining calcium homeostasis. Elevated levels of serum calcium stimulate the release of calcitonin from the parafollicular C cells of the thyroid gland. Calcitonin works opposite of PTH and calcitriol in the regulatory loop to decrease serum calcium levels via inhibition of osteoclast bone resorption and opposing the effects of PTH on the kidneys, promoting calcium excretion.6
Assessing serum calcium concentrations:
The universally excepted normal range for serum calcium concentration is between 8.5 and 10.5 mg/dL. It is important to keep in mind that a value representing the total serum calcium concentration includes both bound and unbound forms of calcium. In the serum, calcium is bound to plasma proteins, predominantly albumin. Knowing that the ionized, or unbound, form of calcium is the physiologically active form of the electrolyte, abnormal serum albumin concentrations may result in the total serum calcium not accurately reflecting the amount of ionized calcium in circulation. To calculate a value that better represents the physiologically active form of calcium in the body, the corrected calcium equation should be used when albumin concentrations are below 4 g/dL (Figure 1).5
Although patients with higher serum calcium concentrations often present with more severe symptoms of hypercalcemia, the staging system for hypercalcemia is based solely on serum lab concentrations as seen below in Table 1. If serum albumin levels are below 4 g/dL, it is important to use the corrected calcium equation prior to staging the hypercalcemia. Staging of hypercalcemia is important for proper selection of appropriate pharmacologic treatment options, which will be discussed later in this article.6
The two most common causes of hypercalcemia are primary hyperparathyroidism and malignancy. Although these two scenarios account for more than 90% of hypercalcemia cases, vitamin D-related causes, medications, other endocrine disorders, and genetic disorders are also possible etiologies. Thorough patient work-up, including past medical history, physical exam, family history, and medication reconciliation is important in the differential diagnosis.6
Signs and symptoms of hypercalcemia are dependent on the severity and the timing of onset. Patients presenting with mild to moderate hypercalcemia are often asymptomatic. This is especially true for patients with drug-induced hypercalcemia or hyperparathyroidism. Signs and symptoms appear more commonly when the calcium concentration is above 13 mg/dL. In patients with hypercalcemia of malignancy, symptoms can present as anorexia, nausea and vomiting, constipation, polyuria, polydipsia, and nocturia. Patients in hypercalcemic crisis may have more severe symptoms including acute renal failure, and other life-threatening symptoms including arrhythmias, tetany, and pancreatitis.5 A common pneumonic utilized to remember the signs and symptoms of hypercalcemia is “Stones, bones, abdominal moans, and psychiatric groans”.6 These and other signs and symptoms are listed in Table 2.
Treatment of Acute Hypercalcemia
When a patient presents with an initial episode of hypercalcemia, it is important to thoroughly review the patient’s past medical history, complete a physical exam, and review both family and medication history for potential etiologies. If a patient presents with asymptomatic, mild hypercalcemia, observation and correcting reversible causes is recommended over pharmacologic treatment. In patients who are symptomatic or present with moderate to severe hypercalcemia, treatment should be initiated with an appropriate first line therapy, including saline hydration or loop diuretics (Figure 2).5
First Line Treatment
Saline hydration should be initiated upon diagnosis of hypercalcemia with a crystalloid, isotonic fluid, including 0.9% sodium chloride solution, commonly referred to as normal saline. Normal saline (NS) expands intravascular volume, increasing natriuresis and decreasing both sodium and calcium reabsorption in the renal tubule. With initiation of NS, one can expect serum calcium levels to decrease within the first 24-48 hours of treatment. Initially, patients should receive 1-2 L of a NS bolus, which should be followed by a maintenance infusion at a rate of 250-300 mL/hour. Maintenance fluid should be continued until serum calcium levels approach the upper end of the normal limit, or until patients have been appropriately fluid resuscitated. While receiving saline hydration, monitoring should include intake and output, daily weight and electrolyte levels, including sodium, potassium, chloride, bicarbonate, and calcium. Patients receiving saline hydration may experience adverse effects including electrolyte imbalances and fluid overload, warranting caution in patients with a history of chronic kidney disease and heart failure.5
Loop diuretics administered intravenously are an additional option for the first line treatment of acute hypercalcemia. These agents inhibit the reabsorption of sodium and chloride in the ascending loop of Henle and the distal renal tubules in the kidneys, interfering with the sodium-potassium-chloride cotransport system. Because of this inhibition, there is an increase in the excretion of water, sodium, chloride, magnesium, and calcium. Loop diuretics often result in a lowering of serum calcium levels within 1 - 2 hours of therapy. Bumetanide and furosemide are both effective at reducing calcium levels (Table 3).5 Although saline hydration is the treatment of choice for acute hypercalcemia, as mentioned above this treatment option may not be the safest for patients with heart failure or reduced renal function. In these special populations, the addition of loop diuretics may be a great option to reduce serum calcium levels while reducing their risk of volume overload with continual NS hydration. Use of IV loop diuretics is most commonly recommended after proper volume depletion has been restored through saline hydration.7 Necessity for IV loop diuretics should be reassessed frequently as serum calcium levels decrease, in order to avoid adverse effects. Patients on loop diuretics should have blood pressure, renal function, intake and output, electrolytes, and weight monitored periodically while receiving therapy. Potential adverse effects associated with therapy include gout flares, increased urination, and electrolyte imbalances.8,9
Figure 2: Acute Hypercalcemia Treatment Algorithm5
Second Line Treatment
There are several additional treatment options for acute hypercalcemia. Alternative options should be considered when additional calcium lowering is needed following first line options, or in patients who are not candidates for either saline hydration or loop diuretics. Calcitonin antagonizes the effects of the parathyroid hormone, directly inhibits osteoclastic bone resorption, and promotes renal excretion of calcium, phosphate, sodium, magnesium, and potassium by decreasing resorption in the renal tubule. Calcitonin’s onset of action is around 2 hours, and the duration is approximately 48 hours.5,10 Calcitonin is started at a dose of 4 international units/kg body weight SQ every 12 hours. Serum calcium and vitamin D levels should be monitored, and potential adverse effects include flushing, nausea, allergic reactions, and respiratory rhinitis.5,10
Bisphosphonates are another alternative option for treatment of hypercalcemia, as they inhibit bone resorption by absorbing to calcium phosphate and preventing it from dissolving in bone. Bisphosphonates also inhibit osteoclast precursors from transforming into functioning osteoclasts. These mechanisms are why bisphosphonate agents fall into the category of antiresorptive therapy.5 Bisphosphonates have a slower onset of action, ranging from 2 - 7 days. Pamidronate and zoledronic acid are intravenous options that may be used for hypercalcemia (Table 4). It is important to note the dosage of zoledronic acid (Zometa®)11,12 for treatment of hypercalcemia, and how it differs from the zoledronic acid (Reclast®)11 recommended dose of 5 mg IV yearly for treatment of osteoporosis. One advantage of pamidronate over zoledronic acid is it can be a single-day therapy option. Serum calcium, potassium, magnesium, phosphate, creatinine, and vitamin D should be monitored periodically while using bisphosphonate therapy, and potential side effects include nausea, vomiting, abdominal pain, myalgia, fatigue, dizziness, dyspnea, bone pain, headache, anemia, urinary tract infections, and osteonecrosis of the jaw.5,11,12,13
In addition, glucocorticoids can offer further calcium lowering effects. Glucocorticoids reduce gastrointestinal absorption of calcium as well as promote calcium excretion in the urine. They have an onset of action ranging from 3 - 5 days. Some glucocorticoid options include prednisone5, dexamethasone14, methylprednisolone15, and hydrocortisone16 (Table 5). Patients taking glucocorticoids should monitor their blood pressure, blood glucose, and weight while on therapy. Potential adverse effects include insomnia, abdominal pain, osteoporosis, immunosuppression, hyperglycemia, hypertension, and psychiatric disturbances.7
Gallium nitrate is not commonly used for treatment of hypercalcemia, but has been historically used in the treatment of symptomatic cancer-related hypercalcemia.5 Dosing of gallium nitrate for treatment of hypercalcemia is typically 100 – 200 mg/m2 IV daily for a total of 5 days.6 Hemodialysis may be indicated in some patients with acute hypercalcemia as a last-line treatment option.5 Hemodialysis may be more commonly considered in patients with renal failure or cardiac comorbidities in whom saline hydration or loop diuretics may not be safe or appropriate options to treat hypercalcemia. Low calcium bath products may be used to treatment of hypercalcemic crisis, and may provide up to one-third clearance of serum calcium concentrations. Calcium free dialysate may lead to hemodynamic instability, and thus is not recommended.18
Treatment of Chronic Hypercalcemia
Patients with non-reversible causes of hypercalcemia may require maintenance therapy to prevent recurrent episodes. The two most common causes of chronic, persistent hypercalcemia are primary hyperparathyroidism (PHPT) and hypercalcemia of malignancy (HCM). PHPT and HCM can be related to over 90% of hypercalcemia cases. The epidemiology of PHPT in the United States ranges from 10-30 cases per 100,000 people, and hypercalcemia associated with cancer occurs in 20-40% of patients during the course of disease.5 Compared to PHPT, HCM is typically associated with more severe clinical symptoms of hypercalcemia and can often be an oncologic emergency. Because of this, HCM is more often diagnosed while patients are hospitalized in contrast to PTPT which is more often diagnosed via laboratory work in the ambulatory care setting. Figure 3 can be useful in the evaluation and treatment of hypercalcemia in patients with or without cancer.
Figure 3: Evaluation and Treatment of Chronic Hypercalcemia19
PTH levels above 20 pg/mL are considered unsuppressed, or high PTH levels in the setting of elevated serum calcium levels. Patients with PHPT are often asymptomatic, and hypercalcemia is usually found incidentally with routine laboratory monitoring. Upon advent of the commonly used electrolyte panel, the diagnosis of PHPT increased. Surgical evaluation should be considered in all, but especially symptomatic patients diagnosed with PHPT. A parathyroidectomy may be indicated in patients less than 50 years old, with a serum calcium level greater than 1 mg/dL above the normal range, bone health risk (osteoporosis or vertebral fracture), or impaired renal function.19
Patients who are not surgical candidates may receive pharmacological management, including bisphosphonates, denosumab, or cinacalcet.19 Cinacalcet is a calcium-sensing receptor agonist that increases the sensitivity of the calcium-sensing receptor on the parathyroid gland, lowering PTH secretion, serum calcium, and serum phosphate levels. Cinacalcet is dosed at 30 mg orally twice daily with a maximum dose of 90 mg three-four times daily. Doses can be adjusted every 2 – 4 weeks. While taking cinacalcet, patients should monitor for potential adverse effects, including hypotension, headache, fatigue, gastrointestinal effects, depression, bone fractures, muscle spasms, weakness, myalgia, and dyspnea.5,20 Information regarding treatment with denosumab can be found in the HCM section below.
Hypercalcemia of Malignancy (HCM)
The two most common causes of HCM are humoral and local bone osteolysis. Although less common, lymphomas may also cause excess calcitriol production, leading to hypercalcemia. If patients present with hypercalcemia, and PHPT has been ruled out, workup for hypercalcemia etiologies in these patients should include identifying a potential underlying malignancy. Presenting symptoms of HCM include the expected gastrointestinal upset, anorexia, polydipsia, polyuria, hypotension, bone pain, fatigue, and confusion, but may also include more severe signs and symptoms such as renal failure, cardiac failure, coma, and even death. The severity of symptomatic presentation correlates to both the degree of hypercalcemia and the rate at which serum calcium has risen.19
After ruling out PHPT as the cause of hypercalcemia, the next important step is assessment of serum PTH-related protein (PTHrP) levels. The secretion of PTHrP from malignant tumor accounts for 80% of HCM cases, and this syndrome is referred to as humoral hypercalcemia of malignancy. The most common tumors associated with this syndrome include squamous cell carcinoma of the lung, head and neck, esophagus, skin, or cervix, as well as carcinomas of the breast, kidney, prostate, or bladder. PTHrP is a protein produced by certain cancer cells, and a serum level > 2.5 pmol/L is significant. As the name implies, PTHrP has effects similar to PTH in some tissues. At the kidneys, PTHrP increases the reabsorption of calcium. By stimulating osteoblasts to secrete RANKL, PTHrP also leads to increased serum calcium levels by stimulating the differentiation of osteoclast precursors into osteoclasts, leading to increased bone resorption. PTHrP assays have become increasingly more accurate and should be checked in all patients with suspected HCM.19
HCM secondary to osteolysis mediated by local tumor cell secretion of osteoclast-activating cytokines is most commonly seen in patients with breast cancer and multiple myeloma. Of note, the mechanism of this form of HCM is not a direct tumor invasion and degradation of bone tissue, but instead caused by cytokines such as IL-1, IL-6, and TNF-alpha acting similarly to PTH to stimulate bone resorption via osteoclasts. Clinically, the differential diagnosis of humoral HCM and bone osteolysis relies upon PTHrP levels, as they will be low in the setting of bone osteolysis. Although associated with less than 1% of HCM, excessive production of calcitriol may lead to hypercalcemia in patients with malignancies, most often seen with lymphomas.19
The primary focus of treating HCM should include treatment of underlying malignancy if able. Patients presenting with acute, symptomatic hypercalcemia should be treated via the algorithm outlined in the acute hypercalcemia section (Figure 2). For treatment and prevention of chronic hypercalcemia, anti-resorptive agents such as intravenous bisphosphonates, denosumab, and calcitonin, as well as glucocorticoids are recommended alongside malignancy treatment. Approved by the FDA in 2014 for treatment of HCM, denosumab is a human monoclonal antibody which binds to RANKL, preventing RANK from binding to osteoclasts. This inhibition leads to decreased osteoclast resorption of bone.19 Denosumab (Xgeva®) is often recommended in HCM that is refractory to bisphosphonate therapy. With an onset of action around 3 days, denosumab should be administered at a dose of 120 mg SQ every 4 weeks, with additional doses administered within the first month of therapy on days 8 and 15.21 It is important to note that this dosing is different than the dosing of denosumab for treatment of osteoporosis, which goes by the separate brand name Prolia®. Adverse effects of denosumab that have been reported include GI upset, peripheral edema, rash, headache, thrombocytopenia, asthenia, back pain, and osteonecrosis of the jaw. Monitoring for denosumab should include renal function, electrolyte levels, signs of infection, hypersensitivity reactions, and routine oral exams.
Calcium plays an important role in many biologic functions throughout the body, and abnormalities in extracellular calcium concentrations can lead to severe symptoms and even death if not addressed. Within the United States, the most common causes of hypercalcemia include primary hyperparathyroidism and malignancy, with up to one-third of patients with cancer experiencing hypercalcemia at some point during the course of disease. Correction of hypercalcemia may include pharmacologic treatment options such as saline hydration, diuretics, bisphosphonates, and steroids. Assessment and correction of underlying etiologies is just as important as initiating pharmacologic treatment to prevent further occurrences of hypercalcemia.
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By: Kacee Verhovec, PharmD; PGY1 Community-Based Pharmacy Resident
Mentor: Michelle Jeon, Pharm.D., BCACP, Walgreens/St. Louis College of Pharmacy
In August 2019, concerns about electronic cigarette use began to grow after the first death associated with the inhaled product was reported.1 Within several months, the death toll reached 68 in February 2020 with nearly 3,000 additional cases leading to hospitalization.2 Unfortunately, safety concerns continued to grow as electronic cigarettes gained popularity in the younger population. How did we get to this point?
The History of Smoking:
In 1492, Christopher Columbus “sailed the ocean blue,” bringing tobacco leaves back to Spain acquired from the Native Americans. Popularity quickly spread throughout Spain and all of Europe. During this time, many believed smoking had curative properties. As a result, tobacco was considered a protected crop and was rationed during times of war. It wasn’t until 1795 when tobacco smoking was linked to a negative health outcome: lip cancer.3 This was followed with a link to lung cancer in 1912. However, this was not reported by the United States (US) Surgeon General until 1964. Shortly after, secondhand smoke was also linked to cancer, leading to age limits on tobacco sales (age 18 beginning in 1992), required health warnings, public smoking bans, and smoking cessation assistance with the nicotine patch first released in 1992.4
In 2003, Chinese pharmacist Hon Lik invented the first electronic cigarette. He was inspired to create this product after witnessing his father die from lung cancer caused by long-term heavy cigarette smoking, in attempts to create a product to help others quit. Shortly after its release, countries around the world began implementing bans on these products, however regulation of these products by the Food and Drug Association (FDA) was implemented nearly 10 years after its release. Age limits for purchasing electronic cigarette products were not implemented until 2018, leading to younger people utilizing these products often due to ease of access.5 Bans of these products did not occur in the US until June 2019 in San Francisco. The first death linked to electronic cigarette use was reported in August 2019.6,7 At the present time, Federal tobacco sales increased to 21years old in December 2019, but questions remain surrounding the future of electronic cigarettes, their regulations, and if they have positive benefit.8
The Pathophysiology of Nicotine Addiction:
The most recent data from the Centers for Disease Control (CDC) indicates that 14% of the US population are smokers, which has been on a decline since 2005. It is estimated that 70% of this population would like to quit and many find the quitting process to be difficult.9
Nicotine is a sympathomimetic that activates the nicotinic receptors in our bodies and most notably, in our brain within the cerebral cortex and limbic system. With this activation, neurotransmitters such as dopamine are released, leading to the rewards pathway and effects of elevated mood and reduced tension, this pathway is shown in Figure 1 above. As nicotine levels decrease after metabolism, the body requires more to continue receptor activation and neurotransmitter release.10 Without more nicotine, the body will go through withdrawal leading to side effects such as cravings, anxiety, and irritability, most frequently leading to additional nicotine intake to relieve these effects. Symptoms typically occur within 1-2 days without nicotine. If nicotine is not replaced, these withdrawal symptoms typically last 2-4 weeks depending on the length of time a person has smoked and the amount a person typically smoked in order to achieve the positive nicotinic effects.11,12
The amount of nicotine required to achieve its desired effects depends on the length of time a person has smoked as nicotinic receptors eventually become desensitized. Desensitization of nicotine receptors requires more nicotine to achieve the positive effects. Utilizing this additional nicotine due to desensitized nicotinic receptors is not associated with the negative side effects typically associated with high amounts.13 Tolerance is defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as having one or both of the following: 1. “absence of nausea, dizziness, or other characteristic symptoms despite using substantial amounts of nicotine” or 2. “diminished effect observed with continued use of the same amount of nicotine-containing products.”14 Because of this cycle, smokers tend to have a difficult time with quitting. The CDC estimates that 87% of adult smokers started smoking as adolescents.9 Increased length of smoking history may cause quit attempts to be even more difficult with resulting increased severity of withdrawal symptoms.13 Cigarette smokers have attempted to quit by utilizing electronic cigarettes as many of these products contain nicotine allowing smokers to continue obtaining nicotine without the additional harmful components of cigarettes such as tar.15
A survey of adult electronic cigarette (also known as e-cigarettes) users conducted in the Netherlands and Belgium identified the number one reason for e-cigarette use was to quit smoking. 94% of those surveyed believed electronic cigarettes were “healthier” than smoking cigarettes.15 A following CDC survey reported that the most popular reason for adolescent e-cigarette users initiating use was curiosity.16
Images of a Tanks and mods, rechargeable e-cigarette, and a disposable e-cigarette.
There are several different types of electronic cigarettes available in various designs, but each electronic cigarette has three key components to them: battery, atomizer, and inhaler. The battery allows for the electronic cigarettes to heat up the liquid. The atomizer contains coils attached to the battery that are soaked in the liquid to be vaporized. When these coils are heated, they subsequently heat the liquid atop the coil itself. Heating this liquid results in evaporation. The vapor is then contained within the atomizer allowing this to eventually be inhaled. The inhaler is the mouthpiece used to inhale the vapor contained within the atomizer.17
The liquid added to the device that is to be vaporized (also known as e-liquid) may contain a variety of ingredients.18 The majority of e-liquids contain a base, most frequently containing distilled water, propylene glycol, and vegetable glycerin, a flavoring, and at times nicotine or tetrahydrocannabinol (THC). Not all e-liquid contains nicotine or THC as some are designed to contain only flavoring to attract users.18,19
E-liquids containing nicotine typically equate to one pack of cigarettes per milliliter of liquid (although this may vary depending on the concentration purchased); most bottles of liquid contain around 30 milliliters. One bottle typically costs around $15, making this an attractive option for those attempting to quit for financial reasons.20
Potential Benefits of Electronic Cigarette Use:
At this time, numerous studies have been conducted that suggest the utility of e-cigarettes for smoking cessation. One study published in February 2019 in the United Kingdom, compared the safety and efficacy of e-cigarettes to traditional nicotine replacement therapy for smoking cessation. This study enrolled adult smokers willing to quit in an unblinded randomized controlled trial.21
At 4 weeks, both products led to abstention from cigarettes, but the e-cigarette group showed statistically significant rates of abstention compared to the traditional NRT group, data shown in Figure 3 below. At 52 weeks, both groups continued to show a decline in those continuing to abstain from cigarette smoking, however the e-cigarette group continued to have a higher percentage of patients abstaining from cigarette use. This study also showed improvements in side effects frequently caused by cigarette smoking in the e-cigarette group such as increased phlegm production, cough, wheezing, and dyspnea shown in Figure 4; this was hypothesized to be associated with the higher amount of patients abstaining from cigarette smoking in the e-cigarette group.21
This study also identified that 80% of those in the e-cigarette group who remained abstinent to cigarettes at 52 weeks were still continuing to use the e-cigarette device compared to roughly 9% in the traditional nicotine replacement product group shown in Figure 5. Leading the authors to question if e-cigarettes were a replacement to cigarette smoking rather than a tool for overall complete cessation.21
Risks of E-Cigarette Use:
In the previous study discussed, the e-cigarettes did not come without side effects. Figure 6 lists the most common side effects cited included nausea, throat/mouth irritation, and sleep disturbances; however, throat/mouth irritation was the only side effect cited to be more common in the e-cigarette group compared to the traditional nicotine replacement therapy group.21 Outside of this study, e-cigarettes have also been linked to endothelium changes in vessels, seizures, and physical injuries due to device malfunctions.22,23,24 The vapors produced by these products, including the second-hand smoke, contain harmful organic and inorganic chemicals such as formaldehyde and heavy metals.25 The deaths reported in August 2019 were associated with a peculiar lung injury only present in those with a recent history of e-cigarette use. Since then, the injury has been named “E-cigarette or vaping product use-associated lung injury” or “EVALI.”1,26
EVALI is diagnosed by the following: having symptoms consistent with EVALI, e-cigarette use within the last 90 days, and abnormal chest imaging (most frequently as bilateral ground glass opacities in the lower lobes). Symptoms of EVLAI are not nonspecific. The majority of patients diagnosed show respiratory symptoms such as dyspnea, hypoxemia, cough, chest pain, and hemoptysis. However, 77% of patients also have gastrointestinal complaints such as nausea, vomiting, and diarrhea as well as symptoms such as fatigue, headache, and weight loss. Patients may also show non-specific signs and symptoms such as fever, leukocytosis, and elevated liver function tests. Case reports led to questions of what would be causing such injuries. In the first case series addressing the issue, 89% of those studied reported THC product use within their devices.26,27
THC has become popular over the last few years with more states legalizing its use. A survey attempted to determine what attracted users of THC products within e-cigarettes to use these products instead of smoking cannabis products. The survey revealed using e-cigarettes (or vaping) THC tasted better or cleaner than other routes. Other reasons to vape THC products instead of smoking them included this was easier to conceal as the smell is not as strong, it is convenient, and it produces a stronger high than other routes.28
Some patients presenting with EVALI who reveale a history of vaping THC products underwent bronchi alveolar lavage (BAL) revealing a non-infectious disease, non-specific inflammation, and increased levels of lipid-laden alveolar macrophages.26 Alveolar macrophages act as the first line of defense for the lungs, clearing foreign bodies including external lipids. While it is normal to have a small amount of lipid-laden macrophages on the results of a BAL, these patients showed an excessive amount. This finding led to further testing of vaped THC products.29 It was identified that 94% of these products contained vitamin E acetate, a lipid containing additive.26 While the most popular THC-containing e-liquids did not report such additives, many did display warnings of fake products being sold.30,31 THC solutions have a naturally high viscosity, especially in comparison to nicotine solutions. Vitamin E acetate has a viscosity similar to THC and is often used as a thickening agent in fake products to deceive consumers.32
Vitamin E acetate is a problem in the lungs for two main reasons. First, vitamin E acetate has shown to penetrate lung surfactants, leading to a loss of surface tension. This eventually may result in damaged lung tissue, and increased risk of a collapsed lung. Another mechanism in which vitamin E acetate damages the lungs is when heated, vitamin E acetate breaks down into 30-ketene, a known lung irritant. This metabolite can cause inflammation in the lungs and eventual damage to the tissue.32 When mice were exposed to vitamin E acetate aerosols, the BAL performed showed very similar results to humans including this increase in lipid-laden alveolar macrophages.33
It is important to note that although there have been some potential benefits with utilizing these products, in particular for smoking cessation, there are risks that we currently know and risks we may not. Centuries passed before negative health effects were definitively associated with cigarette smoking, while e-cigarettes have only been around since 2006.5
Rules and Regulations of Electronic Cigarettes:
FDA regulations on e-cigarette products did not occur until 2016, about ten years after its introduction to the United States. The federal minimum age limit for purchase was set in 2018 at 18 years old. 2016 FDA regulations cited that any product on the market prior to February 15, 2007 was exempt from FDA regulations and products on the market after that date was considered a new product. New products must be authorized by the FDA by September 9, 2020 to continue to be produced and sold.34 Therefore, there may still be products currently being sold that have not been approved by the FDA for sale.35 This approval process requires manufacturers to provide paperwork reporting product labeling, ingredients, advertisements, and warning label display.34
On December 20, 2019, the Federal Food, Drug, and Cosmetic Act was amended to increase the federal minimum age limit for purchase of tobacco products to 21, increasing the age from the previous limit of 18 years old.36 E-cigarettes and e-liquid are currently regulated as tobacco products, only if they contain nicotine.34 In 2019, 27% of high school students reported using e-cigarettes.37 To deter this age group from these products, several legislations at the federal and state level have been introduced, including a call for increased taxes on sale of these e-cigarettes and for banning of flavored e-liquids. Currently, Missouri has not implemented either of these.38
CDC Recommendations for E-Cigarette Use:
The CDC recognizes the potential risks and benefits associated with e-cigarette use and have recommended those not currently using combustible or non-combustible products such as e-cigarettes should not start using them. Pregnant women, adolescents, and young adults should never partake in vaping any products. However, those currently using e-cigarettes specifically for smoking cessation should not go back to using combustible products, should not utilize both e-cigarettes and combustible products at the same time, and should ensure e-liquids or devices come from a reputable source such as in-person e-cigarette or vape shops rather than online dealers, family, or friends. Other FDA-approved smoking cessation products would be preferred. The CDC also recommends against the use of THC products within e-cigarettes, especially those containing vitamin E acetate.39 The World Health Organization addresses these concerns similarly, however they address the lack of data behind e-cigarettes for smoking cessation and recommends currently known effective interventions for smoking cessation instead.40
The American Cancer Society agrees with the recommendations provided by the CDC however they also explicitly state being against the use of e-cigarettes for smoking cessation until a product is approved by the FDA to be used for this purpose alone.41 The American Lung Association states they do not support the use of e-cigarettes even for smoking cessation. They believe there should be increased regulations in regards to e-cigarettes.42 In addition, the American Medical Association agrees with these recommendations, calling for a total ban on e-cigarette products not meeting FDA approval as cessation tools and currently there are no such products available on the US market.43
The current recommendations for use from numerous health organizations all agree people should not start using e-cigarettes leisurely and agree there are still unknowns associated with the devices’ safety, however recommendations regarding cigarette smoking cessation is still widely controversial. It is important for pharmacists to provide as much education to patients regarding the use of e-cigarettes so users are fully informed of their widely unknown risks and possible benefits.
By Nathan Hanson, PharmD, MS, BCPS; Healthtrust Supply Chain
Every time we turn on the TV or Twitter feed, we face a barrage of facts and opinions about rules. From masks to sports to school policy to social justice, it is impossible to ignore the fact that rules and rule-makers play a huge role in our everyday lives. It is also an interesting case study in the interplay among the rules at the federal, state, and local level, as well as how those rules play out in the real world of businesses and organizations and the family. When done well, rules level the playing field and keep us safe. While there are certainly huge differences in opinions about the definition of ‘good rules,’ everyone can agree that more input from more voices is the best way to create them. This is especially true when the data is conflicting and the basic understanding of the situation changes frequently. This type of scenario calls for leaders of bold vision who also ask questions and listen. Put simply, regulation in uncertain times requires participation. As MSHP members, we can participate by staying knowledgeable and getting involved.
Subscribe to newsletters, such as the Board of Pharmacy, MSHP, and ASHP. For example, our Missouri Board of Pharmacy has been very active as they have provided flexibility to Missouri pharmacies to deal with the pandemic response, and all of the information you need to know has been posted on the website and sent out via newsletters. You can subscribe to the ASHP Daily Briefing as well as Advocacy Updates and other options through your account NewsLink settings. You can also participate in the conversation on ASHP Connect. This MSHP newsletter is always informative, and MSHP is expanding our use of social media platforms to share information. Joint Commission, NABP, and USP also provide useful information. Read through the Pharmacy Practice Guide and the Department of Health hospital pharmacy rules. Schedule time on your work calendar or your personal calendar to catch up on current events in pharmacy and actually read those articles that are sitting in the “Read Me” folder. A small investment of time, consistently applied over weeks and months, will compound into a solid foundation of understanding.
Participate at your workplace as they work out the best plan for providing excellent pharmaceutical care in the ever-changing COVID landscape. Provide your input and your questions to the discussions about how to ensure that care, respect and opportunity is experienced by all patients and teammates, regardless of race. Join a committee or attend a live or virtual event to get involved with MSHP, with your regional chapter of MSHP, or with ASHP. Find out who your legislators are (link), and contact them. Let them know that pharmacists play an important role for our patients, and if we are given provider status we could do even more. It is an election year, so get educated and vote.
Uncertain times call for participation at all levels. As pharmacists, we have a responsibility to stay knowledgeable and get involved to ensure that our patients get the care that they need.
By: Nathan Hanson, PharmD, MS, BCPS
Have you ever wondered what the public policy committee does? As our previous article explained, you can learn about pharmacy by comparing it to sports, and in both settings, rules matter. (That has been taken to an extreme lately, because laws and rules have kept elite athletes on the sidelines!) The Public Policy Committee keeps an eye on 3 basic levels of pharmacy rules: Legislative, regulatory, and association. It has been a crazy couple months in healthcare rules, so we have put together just a few updates in all 3 spheres. Remember, MSHP matters. Collaboration is a priority. Things are changing. Stay engaged!
Legislative: Elected officials and votes
The Missouri legislative session wrapped up, after being significantly disrupted by COVID. Many of the legislative priorities were put on the backburner (think 2021), and a statewide Prescription Drug Monitoring Program was again voted down. However, a helpful proposal was passed that will make it safer for our patients to receive specialized compounded medications. When it has been signed by the governor MSHP will provide more information about how to implement this change. This is a patient safety improvement, and it was a wonderful example of MSHP working together with the Missouri Pharmacy Association and the Missouri Hospital Association to make a positive impact. We truly appreciate their leadership on this issue!
Regulatory: Government employees, inspectors, and boards
The Missouri Board of Pharmacy did an amazing job of responding to the public health emergency. They held multiple meetings and worked tirelessly over the past 3 months to ensure that they had done everything they could do to remove regulatory barriers that might get in the way of providing safe care to patients during the COVID emergency. Thankfully, many of the worst case scenarios did not materialize, but Missouri made a strong effort to be ready. The 2008 USP 797 standards will continue to be in effect, as the revisions go through the committee again. The FDA has finalized a document outlining clear regulatory cooperation with the state boards for interstate compounding. Each state board will review the document to determine if it meets the needs of their state.
Associations: Groups of thought leaders, providing best practices and direction for the profession
The 2020 ASHP House of Delegates has approved a slate of professional policies (link). These are designed to clearly explain the wishes and priorities of the 55,000 ASHP members. They are developed and approved with input from elected members from each state, including member of MSHP. MSHP Board of Directors approved guidance for safe implementation of a technician product verification program within the hospital setting. This guidance document was put to the membership for a vote and was passed. Stay tuned for more information.