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The layered learning model (LLM) is a well-established teaching approach designed for attending preceptors to train post-graduate learners and to precept students. The adaptation of a LLM to a virtual exchange program has not been previously described. The purpose of this study was to evaluate the effectiveness of the longitudinal virtual international exchange program in applying principles of the LLM to multiple levels of learners and instructors at West Virginia University (WVU) School of Pharmacy and Kitasato University (KU) School of Pharmacy.The online survey piloted the impact of applying the LLM to virtual international exchange sessions on improving participant knowledge in pharmacy practice, pharmacy education, cultural practices, and cultural awareness. The survey questions assessed the program's structure and effectiveness in achieving learning outcomes related to pharmacy residency topics and cultural competency using a five-point Likert scale.Median scores of the effectiveness of the virtual international exchange program structure were high (≥ 4.0). Two questions evaluating the use of the LLM had median scores of 4.0. All nine residency-related questions were rated ≥3.0. The median scores for three questions evaluating small group discussions and the use of the LLM were rated significantly higher by WVU participants than KU participants. There were no significant differences in program structure and learning outcome ratings between participant groups (student vs. resident/fellow vs. preceptor/faculty).Application of the LLM to the virtual international exchange program was positively received by participants, particularly by United States participants.

Background: Clinical pharmacists play pivotal roles in multidisciplinary heart failure (HF) teams through the management of HF pharmacotherapy, but no study has examined the economic impact of HF ambulatory clinical pharmacists in an advanced HF clinic. Objective: The objective of the study was to evaluate the economic impact of HF ambulatory clinical pharmacist interventions in an advanced HF clinic using a cost-benefit analysis. Methods: This prospective observational study detailed HF ambulatory clinical pharmacist interventions over 6 months in an advanced HF clinic in a single-center tertiary teaching hospital. The economic impact of the interventions was estimated based on the indirect cost savings with pharmacist interventions and direct cost savings recommendations. A cost-benefit analysis was performed to assess the cost of delivering the interventions compared with the benefits generated by clinical pharmacists. Results were reported as a benefit-cost ratio and net benefits. Results: HF ambulatory clinical pharmacists made a total of 2,361 provider-accepted interventions over 6 months. Overall, the 3 most common intervention types were medication reconciliation (28.7%), dose change (20.8%), and addition of medication (12.3%). Anticoagulation (21.2%) was the most common intervened class of medication, followed by sodium-glucose cotransporter-2 inhibitor (12.3%) and angiotensin receptor neprilysin inhibitor (9.2%). The total net benefits were $55,553.24 over 6 months and the benefit-cost ratio was 1.55. Conclusion and Relevance: The addition of cardiology clinical pharmacists to an advanced HF clinic may be financially justified and cost-beneficial.

Aim: To identify knowledge gaps in heart failure (HF) research among women, especially postmenopausal women. Materials & methods: We retrieved HF articles from PubMed. Natural language processing and text mining techniques were used to screen relevant articles and identify study objective(s) from abstracts. After text preprocessing, we performed topic modeling with non-negative matrix factorization to cluster articles based on the primary topic. Clusters were independently validated and labeled by three investigators familiar with HF research. Results: Our model yielded 15 topic clusters from articles on HF among women. Atrial fibrillation was found to be the most understudied topic. From articles specific to postmenopausal women, five clusters were identified. The smallest cluster was about stress-induced cardiomyopathy. Conclusion: Topic modeling can help identify understudied areas in medical research.

Background There is no standard approach for managing the use or dose of loop diuretics after initiating sacubitril/valsartan. Objective To investigate longitudinal trends in loop diuretic therapy use and doses during the initial 6 months following sacubitril/valsartan initiation. Methods This retrospective cohort study included adult patients who were initiated on sacubitril/valsartan in cardiology clinics. Inclusion criteria were patients diagnosed with heart failure with reduced ejection fraction (ejection fraction ≤40%) and initiated on sacubitril/valsartan in an outpatient setting. We investigated longitudinal trends in the prevalence of loop diuretic use and furosemide equivalent dose at baseline, 2 weeks, 1 month, 3 month and 6 months following sacubitril/valsartan initiation. Results A total of 427 patients were included in the final cohort. Compared to the baseline loop diuretic use and dose, there were no significant longitudinal changes in the prevalence of loop diuretic use or the furosemide equivalent dose over the 6 months following sacubitril/valsartan initiation. The use of sacubitril/valsartan was not significantly associated with reductions in the use or dose of loop diuretics over a 6-month follow-up period. Conclusion The use of sacubitril/valsartan did not significantly change the use or dose of loop diuretics over 6-month follow-up period. Initiation of sacubitril/valsartan may not need a pre-emptive loop diuretic dose reduction.

Background Limited evidence is available regarding low (24/26 mg) and middle (49/51 mg) doses of sacubitril/valsartan. Objectives The purpose of this study was to investigate the effect of sacubitril/valsartan dose on heart failure (HF) hospitalization and mortality in patients with HF with reduced ejection fraction (HFrEF). Methods A retrospective multicenter cohort study compared 3 doses of sacubitril/valsartan in patients with HFrEF. The coprimary outcomes were all-cause mortality and rehospitalization for HF. Propensity matching analysis was performed. Results Of 721 eligible patients, propensity matching created a cohort with an effective sample size of 652 (24/26-mg group [n = 326], 49/51-mg group [n = 147], 97/103-mg group [n = 179]). The HF hospitalization rates were 29.14% in the 24/26-mg group, 19.51% in the 49/51-mg group, and 16.10% in the 97/103-mg group (24/26 vs 49/51 mg: HR = 1.56, 95% CI = 1.04-2.34; 24/26 vs 97/103 mg: HR = 1.79, 95% CI = 1.18-2.73; 49/51 vs 97/103 mg: HR = 1.15, 95% CI = 0.70-1.89). All-cause mortality rates were 29.63% in the 24/26-mg group, 17.58% in the 49/51-mg group, and 9.27% in the 97/103-mg group (24/26 vs 49/51 mg: HR = 1.67, 95% CI = 1.07-2.59; 24/26 vs 97/103 mg: HR = 2.56, 95% CI = 1.54-4.24; 49/51 vs 97/103 mg: HR = 1.54, 95% CI = 0.84-2.82). Conclusion and Relevance Sacubitril/valsartan 97/103- or 49/51-mg dose is associated with a lower mortality or hospitalization rate for HF in patients receiving sacubitril/valsartan compared with the 24/26-mg dose group.

The International Society of Thrombosis and Haemostasis recommends warfarin therapy over direct oral anticoagulants (DOACs) in patients with a body mass index >40 kg/m2 or weight > 120 kg due to limited clinical data in morbidly obese patients. The aim of the meta-analysis was to compare DOACs with warfarin in morbidly obese patients with atrial fibrillation (AF) and to optimize an anticoagulation therapy in the population. MEDLINE, Embase, Google Scholar, Web of Science, and Cochrane Library database searches for relevant articles through December 23, 2019 were performed. Total 5 studies for the event rate of stroke or systemic embolism (SE) and 4 studies for major bleeding were included in the meta-analysis. It showed that there was no statistically significant difference in stroke or SE event rate between the DOAC and warfarin groups (odds ratio: 0.85; 95% confidence interval: 0.60, 1.19; p = 0.35; I2 = 0 %). The DOAC use was significantly associated with a lower major bleeding event rate compared the warfarin group (odds ratio: 0.63; 95% confidence interval: 0.43, 0.94; p = 0.02; I2 = 30%). In conclusion, DOACs should be considered as an oral anticoagulant for preventing stroke or SE in morbidly obese patients with AF. A randomized controlled trial comparing a DOAC with warfarin is needed to confirm our meta-analysis results in morbidly obese patients with AF.

Sacubitril/valsartan is an angiotensin receptor/neprilysin inhibitor that the Food and Drug Administration has indicated to reduce the risk of cardiovascular hospitalization and death in patients with left ventricular ejection fraction below normal and with no specified ejection-fraction cut-off. However, clinically significant patient groups were excluded or minimally represented in sacubitril/valsartan's pivotal clinical trials. Clinicians often encounter scenarios in which a sacubitril/valsartan off-label use may be beneficial, but limited resources are available to evaluate the efficacy and safety in these patients. This state-of-the-art review describes contemporary literature for sacubitril/valsartan Food and Drug Administration off-label indications to help clinicians assess its appropriateness in these selected, clinically important groups of patients: those with acute decompensated heart failure, acute coronary syndrome, peripartum cardiomyopathy, chemotherapy-induced cardiomyopathy, adult congenital heart disease, cardiomyopathy in dialysis patients, right ventricular failure, or durable left ventricular assist device.

Introduction: Unfractionated heparin (UFH) has traditionally been the agent of choice in patients on extracorporeal membrane oxygenation (ECMO). However, direct thrombin inhibitors (DTI) have recently garnered more attention in ECMO because of their advantages over UFH. Given the heterogeneous results of multiple recent published studies, we performed a meta-analysis to describe pooled outcomes between bivalirudin and UFH anticoagulation in patients on ECMO. Methods: Relevant studies were identified from MEDLINE and Google Scholar database searches through April 23, 2022. The primary efficacy outcome was thromboembolism (TE), and secondary efficacy outcomes included all-cause mortality and circuit thrombosis. The primary safety outcome was major bleeding. Results: A total of 6 studies were included in the meta-analysis. Bivalirudin use was associated with significantly lower risk of TE (OR 0.61; 95% CI 0.38-.99; P = .05; I2 = 0%) and circuit thrombosis (OR 0.51; 95% CI .32-.80; P = .004; I2 = 0%) compared with UFH. There was no significant difference in all-cause mortality risk (OR 0.75; 95% CI .52−1.09; P = .13; I2 = 30%) between the bivalirudin and UFH groups. No significant difference in the risk of major bleeding between 2 groups was found (OR 0.67; 95% CI 0.25−1.81; P = .43; I2 = 80%). Conclusion: These data support that bivalirudin is a reasonable alternative to UFH in patients on ECMO. Randomized controlled trials are needed to confirm bivalirudin’s efficacy and safety results compared with UFH.

In 2016, the International Society on Thrombosis and Haemostasis (ISTH) published guidelines advising caution when using direct oral anticoagulants (DOACs) in patients with morbid obesity due to limited clinical efficacy and safety data supporting their use in this patient population. In this review, we analyzed published articles in the MEDLINE database (from inception through May 29, 2019), and the Cochrane Library, Google Scholar, and EMBASE databases (from inception through April 26, 2019) that evaluated morbidly obese patients with atrial fibrillation (AF) or venous thromboembolism (VTE) who received DOACs. A total of 19 studies, which included pharmacokinetic studies, original phase III trials for the DOACs, post hoc analyses of phase III trials, and retrospective cohort studies, were evaluated. Although currently available data do not indicate that using DOACs in the morbidly obese is problematic, DOAC-specific pharmacokinetic variations have been observed. Additionally, less data evaluating DOAC efficacy and safety exist for VTE treatment compared with the data for stroke prevention in patients with AF. The overall quality of the studies included in this review was low due to limited prospective randomized trial data, limiting the ability to form definitive judgments on efficacy and safety DOACs in the morbidly obese. Continued caution is recommended when considering DOAC use in the morbidly obese, particularly for those requiring anticoagulation for VTE treatment, until additional higher-quality data become available.

Objectives To compare the efficacy and safety of torsemide versus furosemide in patients with heart failure (HF). Data sources Medline, Cochrane Library, Web of Science, and Google Scholar database searches for relevant articles from 1946 to May 2018 were performed with the use of the key words torsemide and furosemide. Study selection Studies were included if they met the following criteria: (1) cohort studies or randomized controlled trials of adult patients 18 years of age or older who received oral torsemide or furosemide for HF with reduced or preserved ejection fraction; and (2) studies that reported mortality rate, rehospitalization rate for HF or cardiovascular disease (CVD), or New York Heart Association (NYHA) functional class changes. Data extraction Efficacy outcomes were mortality from any cause, rehospitalization for HF, rehospitalization for CVD, and NYHA functional class improvement. Safety outcome included hypokalemia. Results In the 5 included studies, there was no significant difference in mortality between torsemide and furosemide (odds ratio [OR] 1.00, 95% CI 0.58–1.72; P = 0.99; I2 = 79%). There was no significant difference in rehospitalization rates for HF (OR 0.79, 95% CI 0.57–1.09; P = 0.15; I2 = 64%) or CVD (OR 0.83, 95% CI 0.62–1.12; P = 0.22; I2 = 40%) between torsemide- and furosemide-treated patients. The use of torsemide was associated with significant improvement in NYHA functional class compared with furosemide (OR 1.44, 95% CI 1.18–1.76; P = 0.0004; I2 = 0%). Conclusion Our meta-analysis showed that torsemide is associated with statistically significant improvement in NYHA functional class for patients with HF compared with furosemide. However, torsemide did not provide significant benefits in reducing mortality or rehospitalization rates for HF or CVD compared with furosemide. The authors suggest switching from furosemide to torsemide in patients with HF not achieving symptomatic control with the use of furosemide despite maximizing guideline-directed medical therapy and furosemide dosing.

Background: Limited evidence regarding the use of guideline directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction (HFrEF) undergoing coronary artery bypass grafting (CABG) is available. Objective: The purpose of this study was to characterize prescription of HFrEF GDMT use before and after CABG. Methods: A retrospective analysis of adult patients with an ejection fraction ≤40% undergoing CABG was performed. The primary objective was to evaluate patients receiving HFrEF GDMT, defined as a heart failure beta-blocker (HFBB) and a renin-angiotensin inhibitor preoperatively and postoperatively. Secondary outcomes included dosing, percent of patients on each individual therapy, mineralocorticoid receptor antagonist (MRA) use, and the combination thereof. The follow up period was 1 year. Results: Thirty-eight patients met criteria for inclusion. Prior to CABG, 52.6% of patients were receiving HFrEF GDMT. The prescribing rate of HFrEF GDMT was not significantly higher at any point within 1 year postoperatively ( P = .299). The rate of renin-angiotensin inhibitors, HFBB, and aldosterone antagonists use significantly increased from 13.2% preoperatively to 36.8% at 1 year after CABG ( P = .022). Doses of individual therapies were not significantly different across all time points preoperatively and postoperatively. Conclusion: HFrEF GDMT use and doses of individual therapies after CABG were not maximized. Collaborative efforts between cardiac surgeons, heart failure cardiologists, and pharmacists could be used to optimize HFrEF GDMT use and dose titration.

Background The appropriateness of direct oral anticoagulant (DOAC) dosing has been the issue in the real-world setting, and inappropriately lower DOAC dose may not be as effective or safe as the standard dose in patients with atrial fibrillation (AF). Multiple real-world studies compared the inappropriately lower DOAC dose versus the standard dose, but their main findings were contradictory. Methods A meta-analysis was performed to compare the efficacy and safety of the inappropriately lower DOAC dose with the standard DOAC dose in patients with AF. Database searches through May 30, 2021 were performed using MEDLINE and Google Scholar. The primary efficacy outcome was stroke or systemic embolism, and the primary safety outcome was major bleeding. The secondary outcome was all-cause mortality. Results A total of 16 studies were included in this meta-analysis. It revealed that the inappropriately lower DOAC dose was significantly associated with a higher event rate of stroke or systemic embolism compared to the DOAC standard dose (OR 1.21; 95% CI: 1.02-1.43; p=0.03; I2 = 66%). There was no significant difference in the major bleeding event rate between these groups (OR 1.03; 95% CI: 0.92-1.15; p=0.62; I2 = 27%). Conclusion and Relevance The inappropriately lower DOAC dose should be avoided to optimize DOAC effectiveness in patients with atrial fibrillation.

In 2 distinct entities, left ventricular noncompaction (LVNC) and peripartum cardiomyopathy (PPCM), routine anticoagulation therapy is often used in current practices. However, our systematic review showed that LVNC itself was not associated with the increase in thromboembolism event rates and therapeutic anticoagulation therapy should not be considered only for LVNC, unless there is risk factor for thromboembolism. Current literature justifies prophylactic therapeutic anticoagulation in LVNC with low left ventricular ejection fraction (EF < 40%) and/or atrial fibrillation. Although not specifically studied, the presence of intracardiac thrombi by echocardiography or other imaging studies should also prompt anticoagulation therapy. There is limited evidence available for the use of anticoagulation in patients with PPCM, but our systematic review showed that anticoagulation should be recommended only for patients with PPCM especially with an EF < 35% until EF is recovered, as well as for patients with PPCM treated with bromocriptine.

No study has systematically evaluated the prevalence and dosages of diuretic use for patients after left ventricular assist device (LVAD) implantation. The primary objective was to characterize chronologic change in prevalence and doses of loop diuretics after LVAD placement. The secondary objective was to identify correlates of actual doses of loop diuretics. We retrospectively reviewed medical records of adult patients with LVAD implantation at the University of Kentucky. Prevalence of diuretic use and furosemide equivalent dose were assessed before LVAD implantation and at seven time points thereafter: 1 week, 1 month, 3 months, 6 months, 1 year, 18 months, and 2 years. Correlation analyses and linear mixed modeling were used to identify correlates of diuretic dose before and after LVAD implantation. Eighty-two consecutive eligible patients were reviewed. The prevalence of loop diuretic use was 95% at baseline but significantly lower than that at all subsequent time points (p < 0.048 for all). Nevertheless, more than half of patients on whom we had such follow-up data were on loop diuretics 2 years after LVAD implantation. Average furosemide equivalent dose was significantly lower at every time point after implantation compared with baseline (p < 0.006 for all). Blood urine nitrogen (BUN) was the most robust predictor of dose after LVAD implant. The prevalence and average furosemide equivalent dose were significantly reduced after LVAD implantation, but the use of loop diuretic remained more than 50% for up to 2 years. Consistent association with BUN may indirectly indicate overuse of diuretics post-LVAD implant.

Objective: To review the current guidelines and published literature in order to identify the evidence-based international normalized ratio (INR) goal in patients with a mechanical aortic valve. Data Sources: Medline/PubMed, Cochrane and Google Scholar database searches for relevant articles from 1946 through March 2017 were executed using the key words “mechanical aortic valve” and “antithrombotic therapy or anticoagulation therapy or warfarin.” Study Selection and Data Extraction: All English-language observational and interventional studies assessing INR goals in patients with a mechanical aortic valve were evaluated. Results: After low thrombogenic valves became standard in the practice, the INR goal decreased to 2 to 3 in low-risk recipients with most of bileaflet mechanical aortic valves. There is a paucity of data to justify the INR goal of 2 to 3 in high-risk patients. Until further higher evidence is available, it is reasonable to target an INR range of 2.5 to 3.5 in patients with risk factors for thromboembolism with low thrombogenic valves, except for On-X valve. The INR goal in high-risk On-X aortic valve recipients can be managed at 1.5 to 2.5 with low-dose aspirin 3 months after valve implantation. Conclusion: The INR goals of 2 to 3 for low risk and 2.5 to 3.5 for high risk should be considered for bileaflet mechanical aortic valve recipients. Additionally, a lower INR goal of 2 to 3 for the first 3 months after valve replacement followed by an INR goal of 1.5 to 2.5 in both low- and high-risk aortic On-X valve recipients may be considered.

Introduction Geographically dispersed patient populations, provider shortages, and deficits in ancillary services makes optimal heart failure care challenging for patients residing in rural communities. Providing effective care to this complex patient population requires significant knowledge, as well as ample time and availability of complementary, ancillary services. We developed a survey for heart failure care providers in rural West Virginia to self report knowledge of guideline directed care and to evaluate access and use of resources necessary for optimal heart failure management. Methods The 2019 West Virginia Practice-Based Research Network (WVPBRN) Collective Outreach and Research Engagement (CORE) Survey was uploaded to REDCap and distributed to healthcare providers in the Network via email, social media postings, and newsletter announcements. Out of Network non-members in West Virginia (WV) were also encouraged to respond. Survey responses were anonymous and later analyzed by the WV Clinical and Translational Science Institute. Results A total of 41 primary care providers (71% physicians and 29% CRNP, PA, or RN) anonymously responded to the survey. While the majority of respondents practice in rural WV counties, 85% practiced within 10 miles of a hospital. Despite this finding, a great majority of respondents were the main provider of heart failure care, with 76% regularly starting or adjusting heart failure medications. Only 21% of providers stated that their patients had echocardiogram performed in a cardiologist office with the remainder being performed at the local hospital. With respect to knowledge of GDMT, 22% felt they had excellent knowledge, 76% had average knowledge and 2% had poor knowledge. Time spent caring for patients was 20 minutes or less by 76% of providers and 63% of them felt that they needed more time to provide the care required of these patients. With respect to access to multidisciplinary care, most providers 71% had adequate access to a pharmacist, but only 27% had access to a dietician. Conclusions Primary care providers appear to provide the majority of care for patients with heart failure in the rural community irregardless of proximity to a hospital. Opportunity exists to increase knowledge in these providers and to provide better access to ancillary services such a as pharmacists and dietitians which could alleviate the perception that more time is required to provide quality care in rural WV.

Pulmonary hypertension (PH) is often caused by left heart disease (LHD) such as heart failure (HF) or valvular heart disease. Historically, few randomized controlled trials have evaluated the off-label use of medications for treating pulmonary arterial hypertension (PAH) in patients with PH-LHD. However, multiple randomized controlled trials have been published over the last decade that investigated their use in patients with PH-LHD. In addition, recent updates in the classification and definitions of PH have led to an improved recognition of PH-LHD phenotypes, notably combined post-capillary and pre-capillary PH and isolated post-capillary PH. In this systematic review, we show that PAH medications should not be recommended in two distinct HF populations: patients with HF without definitive PH diagnosis and patients with isolated post-capillary PH due to HF. In addition, the use of bosentan or macitentan is not recommended in patients with combined post-capillary and pre-capillary PH due to HF, but sildenafil may be considered to improve pulmonary hemodynamics and exercise capacity in patients with combined post-capillary and pre-capillary PH due to HF. Riociguat 2 mg 3 times daily may also be considered to improve pulmonary hemodynamics in patients with combined post-capillary and pre-capillary PH due to heart failure with reduced ejection fraction but not heart failure with preserved ejection fraction. The postoperative use of sildenafil in the setting of PH after valvular heart disease intervention was evaluated. Limited clinical data and safety concern warrants caution with the postoperative use of sildenafil in patients with PH due to valvular heart disease. Despite recent advances in the understanding of PAH medications for patients with PH-LHD, uncertainty remains about their utility in distinct subgroups. Nonetheless, PAH pharmacotherapy should generally be avoided for most patients with PH-LHD.

Purpose This article evaluates the musculoskeletal safety of concomitant therapy with daptomycin and Hydroxymethylglutaryl-coenzyme A (HMG CoA) reductase inhibitors (statins). Summary Often indicated for severe gram-positive infections, daptomycin is commonly administered with statins but there is limited guidance on the appropriate management of concomitant therapy with daptomycin and statins. A narrative review was conducted to review contemporary clinical evidence of the safety of concomitant therapy with daptomycin and statins. A total of 5 studies were identified comparing daptomycin monotherapy versus daptomycin and statin concomitant therapy for the primary outcome of creatine phosphokinase (CPK) elevations in a variety of patient populations with systemic, skin/soft tissue, and bone/joint infections. Of these studies, 4 also compared myalgia or myopathy as a secondary outcome. Case studies, the case-control study and 1 prospective registry comparing statin alone versus daptomycin and statin concomitant therapy were excluded. These studies showed that concomitant therapy with daptomycin and statin was not significantly associated with CPK elevation or higher event rate of myalgia or myopathy, compared to daptomycin monotherapy. Conclusion Published cohort studies do not demonstrate a statistically significant difference in the rate of CPK elevations or musculoskeletal toxicities between patients receiving daptomycin monotherapy and daptomycin plus a statin. Patients receiving statins who start daptomycin therapy should continue statin but with weekly monitoring of CPK levels. Continuation of statins is especially important in high-risk patients receiving statins for secondary prevention for atherosclerotic cardiovascular diseases. If myalgia develops, it is reasonable to evaluate the degree of CPK elevation and reassess the need for statin use during daptomycin treatment.

SummaryWhat is known and objectives There is a lack of consensus regarding optimal anticoagulation regimen and duration for inferior vena cava (IVC) thrombus due to the paucity of clinical evidence. A case of IVC thrombus treated with 3 months of rivaroxaban therapy is reported. Case description Fifty-two-year-old male Caucasian presented following a motorcycle accident, with multiple left rib fractures requiring emergent amputation surgeries. During the hospitalization, he developed IVC thrombosis and completed 3 months of rivaroxaban treatment without any complication. The Doppler images at 6-week, 3-month and 6-month follow-up appointments showed no IVC thrombosis. What is new and conclusion This is the first case of IVC thrombosis successfully treated with rivaroxaban. Further case series and clinical studies are needed to guide the use of direct oral anticoagulants for IVC thrombosis.

Summary: Hypertriglyceridemia and hyperlipidemia are the most remarkable metabolic complications seen with long-term sirolimus therapy. We report the case of a 36-year-old woman status post bilateral lung transplantation on a maintenance immunosuppression regimen of sirolimus, tacrolimus, and prednisone who presented with status migrainosus, chest pain, abdominal discomfort, and triglyceride levels greater than 4425 mg/dL. In previously reported cases of severe hypertriglyceridemia that developed on maintenance sirolimus therapy, plasmapheresis has been utilized as an early strategy to rapidly lower triglycerides in order to minimize the risk of acute complications such as pancreatitis, but our case was managed medically without plasmapheresis. The most recent triglyceride was down to 520 mg/dL 2 months after discontinuation of sirolimus. We estimate the probability of this reaction to sirolimus as probable based on a score of 5 points on the Naranjo scale. This is the first case report to our knowledge that highlights the sole use of oral lipid-lowering drug agents to treat severe hypertriglyceridemia secondary to sirolimus without the use of plasmapheresis. Conclusion: Sirolimus-induced severe hypertriglyceridemia can be managed with oral lipid-lowering agents without plasmapheresis. Clinician needs to be aware of the importance of baseline and regular triglyceride monitoring in patients on sirolimus.

Introduction Currently, the American College of Cardiology (ACC)/ American Heart Association (AHA)/ Heart Failure Society of America (HFSA) guideline recommends replacing angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blocker (ARB) with angiotensin receptor-neprilysin inhibitor (ARNI) to further reduce mortality or heart failure (HF) rehospitalization rate. However, little evidence is available for low (24/26 mg) and middle (49/51 mg) doses because the Prospective Comparison of ARNI with ACE-I to Determine Impact on Global Mortality and Morbidity of Patients with Chronic Heart Failure (PARADIGM-HF) trial required dose titration up to high dose (97/103 mg) prior to randomization. Thus, our study in the real-world setting seeks to evaluate the effect of sacubitril/valsartan dose (low vs. middle vs. target dose) on mortality rate in patients with heart failure with reduced ejection fraction (HFrEF). Methods Patients receiving sacubitril/valsartan diagnosed as HFrEF from July 2015 to December 2019 were included in this retrospective cohort study. Patients receiving sacubitril/valsartan less than 1 year and receiving dialysis were excluded. The primary outcome was all-cause mortality. The follow-up period was up to 3.5 years after sacubitril/valsartan initiation. The hazard ratios and their 95% confidence intervals (CIs) were calculated. The survival data regression analysis using the Cox proportional hazards model was performed to examine the association between Entresto doses and mortality while controlling age, body mass index, brain natriuretic peptide, creatinine, ejection fraction, gender, systolic blood pressure, and prior ACE-I or ARB use. The significant level was set at 0.05. Results A total of 164 patients in 24/26 mg group, 78 patients in 49/51 mg group, and 80 patients in 97/103 mg group were included in this preliminary analysis. The all-cause mortality rate was significantly higher in 24/26 mg group compared with 97/103 mg group (27.4 vs. 11.3 %; hazard ratio = 2.77; 95% CI 1.35-5.67; p=0.0054). There was no significant difference in mortality rate between 49/51 mg and 97/103 groups (12.8 vs. 11.3 %; hazard ratio = 1.08; 95% CI 0.44-2.68; p=0.859). After controlling for the pre-specified variables, the significant difference between 24/26 and 97/103 mg groups was not retained (HR = 3.96, 95% CI 0.435-35.949, p=0.222) but the hazard of mortality at any given time was greatest in 24/26 mg group compared with 49/59 and 97/103 mg groups. Conclusions The results of this study indicate that sacubitril/valsartan 24/26 mg use is a predictor for a higher mortality rate in patients receiving sacubitril/valsartan. The final analysis with a larger sample size will be needed for further investigation.

Introduction The post-hoc study of Valsartan Heart Failure Trial (Val-He-FT) evaluated the effect of body mass index (BMI) on clinical outcomes in patients with HFrEF receiving valsartan. It showed a decrease in mortality rate with increasing BMI. However, limited data is available for the effect of BMI on mortality rate in patients with HFrEF receiving sacubitril/valsartan. The aim of the project is to assess the relationship between BMI and clinical outcomes in patients with HFrEF receiving sacubitril/valsartan. Methods Patients receiving sacubitril/valsartan diagnosed as HFrEF from July 2015 to December 2019 were included in this retrospective cohort study. Patients receiving sacubitril/valsartan less than 1 year and receiving dialysis were excluded. The whole cohort was divided into three groups based on BMI: normal weight group (BMI greater than or equal to 24.9), overweight group (25 greater than or equal to BMI less than or equal to 29.9) and obese group (30 greater than or equal to BMI). The primary outcome was all-cause mortality. The follow-up period was up to 3.5 years after sacubitril/valsartan initiation. Multiple logistic regression analysis was conducted with hazard ratios and their 95% confidence intervals (CIs). Prespecified variables included age, brain natriuretic peptide, creatinine, ejection fraction, gender, sacubitril/valsartan dose, systolic blood pressure, and prior angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blocker (ARB) use. The significant level was set at 0.05. Results A total of 66 patients in the normal-weight group, 92 patients in the overweight group and 162 patients in the obese group was included in this preliminary analysis. There were no significant differences in mortality rates between normal weight and obese groups (24.24 vs. 18.52%; HR 1.57; 95% CI 0.85-2.88), and overweight and obese groups (18.48 vs. 18.52%; HR 1.10; 95% CI 0.61-1.99). After controlling for the pre-specified variables, no significant difference in mortality rate was retained between normal weight and obese groups (HR 0.19; 95% CI 0.02-1.55), and overweight and obese groups (HR 0.49; 95% CI 0.10-2.36). Conclusions This preliminary analysis shows that no association exists between BMI and mortality rate in patients with HFrEF receiving sacubitril/valsartan. The final analysis with a larger sample size will be needed for further investigation.

Objective To report a case of rhabdomyolysis possibly caused by interaction of ticagrelor with high-dose atorvastatin. Summary A 62-year-old woman originally from India underwent uncomplicated percutaneous coronary intervention following ST-elevation myocardial infarction. The patient was discharged on a secondary prevention drug regimen that included ticagrelor 90mg twice daily, atorvastatin 80mg once daily, metoprolol 25mg twice daily, and aspirin 81mg daily. Two months later, the patient was readmitted with complaints of muscle pain, nausea, vomiting, and poor oral intake. The patient was diagnosed with rhabdomyolysis based on her symptoms combined with elevated creatine kinase, urine myoglobin, and serum creatinine. Intravenous fluids were initiated and atorvastatin held. Throughout the second hospital stay, serial laboratory values revealed a decrease in creatine kinase and resolution of acute kidney injury and muscle pain. The patient was discharged on aspirin and clopidogrel. Low-dose statin therapy was started at a follow-up appointment with close monitoring without recurrence of rhabdomyolysis. Results A drug interaction between the cytochrome P450 3A4 inhibitor ticagrelor and substrate atorvastatin 80mg may have precipitated development of rhabdomyolysis in this patient. The probability of this drug interaction is rated as "possible" on both the Naranjo Adverse Drug Reaction Probability Scale and the Drug Interaction Probability Scale. Conclusion Rhabdomyolysis was observed possibly because of a drug interaction between once-daily ticagrelor and atorvastatin 80mg. Clinicians need to be aware of this possible drug interaction via CYP3A4 and potential complications.

We report the case of capecitabine-induced ventricular fibrillation arrest, possibly secondary to type I Kounis syndrome. A 47-year-old man with a history of T3N1 moderately differentiated adenocarcinoma of the colon, status-post sigmoid resection, was started on adjuvant capecitabine approximately five months prior to presentation of cardiac arrest secondary to ventricular fibrillation. An electrocardiogram (EKG) revealed ST segment elevation on the lateral leads and the patient was taken emergently to the cardiac catheterization laboratory. The catheterization revealed no angiographically significant stenosis and coronary artery disease was ruled out. After ruling out other causes of cardiac arrest, the working diagnosis was capecitabine-induced ventricular fibrillation arrest. As such, an inflammatory work up was sent to evaluate for the possibility of a capecitabine hypersensitivity, or Kounis syndrome, and is the first documented report in the literature to do so when evaluating Kounis syndrome. Immunoglobulin E (IgE), tryptase, and C-reactive protein were normal but histamine, interleukin (IL)-6, and IL-10 were elevated. Histamine elevation supports the suspicion that our patient had type I Kounis syndrome. Naranjo adverse drug reaction probability scale indicates a probable adverse effect due to capecitabine with seven points. A case of capecitabine-induced ventricular fibrillation arrest is reported, with a potential for type 1 Kounis syndrome as an underlying pathology supported by immunologic work up.

Objective: To evaluate current clinical evidence for management of oral anticoagulation therapy after gastrointestinal bleeding (GIB) with an emphasis on whether to, when to, and how to resume an anticoagulation therapy. Data Sources: Relevant articles from MEDLINE, Cochrane Library, and EMBASE databases were identified from 1946 through May 20, 2017, using the keywords: gastrointestinal hemorrhage or gastrointestinal bleeding and antithrombotic therapy or anticoagulation therapy or warfarin or dabigatran or rivaroxaban or apixaban or edoxaban.Study Selection and Data Extraction: All English-language studies assessing management of oral anticoagulation therapy after GIB were evaluated. Data Synthesis: A total of 9 studies were identified. Four retrospective cohort studies showed that resuming anticoagulation therapy was associated with significantly lower rate of thromboembolism (TE) in the general population. Meta-analyses and prospective cohort studies also supported this finding. Two retrospective cohort studies indicated an increase in GIB when anticoagulation reinitiation occurred in less than 7 days without a decrease in TE. Resuming therapy between 7 and 15 days did not demonstrate a significant increase in GIB or TE. A large retrospective study showed that apixaban was associated with the significantly lowest risk of GIB compared with both rivaroxaban and dabigatran. Conclusion: Anticoagulation therapy resumption is recommended, with resumption being considered between 7 and 14 days following GIB regardless of the therapy chosen. Data for warfarin management after GIB should be applied with caution to direct oral anticoagulants (DOACs) because of the quicker onset and experimental nature of reversal agents. Apixaban may be a preferred option when restarting a DOAC therapy.

Purpose The pharmacology, pharmacokinetics, clinical efficacy, safety and tolerability, dosing and administration, and place in therapy of selexipag, an orally administered selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension (PAH), are reviewed. Summary The first-in-class oral prostacyclin IP receptor agonist selexipag (Uptravi, Actelion Pharmaceuticals) was approved by the Food and Drug Administration in December 2015. Selexipag is rapidly hydrolyzed to a long-acting metabolite that binds with high selectivity to IP receptors, resulting in vasodilation, inhibition of platelet aggregation, and antiinflammatory effects. Results of a long-term, placebo-controlled, clinical outcomes–driven trial showed that selexipag significantly reduced the occurrence of the composite primary outcome (all-cause mortality and development of PAH-related complications). Selexipag is indicated for use in patients with World Health Organization functional class (FC) II or III disease. The recommended initial selexipag dosage is 200 μg twice daily. Like prostanoid analogs, selexipag has a dose-dependent adverse-effect profile that includes nausea, vomiting, diarrhea, headache, and musculoskeletal pain. Although selexipag offers distinct pharmacologic advantages over other agents for the treatment of PAH, important issues of cost and access must be considered. Conclusion Selexipag is an oral prostacyclin IP receptor agonist approved for use as monotherapy or in combination with other therapies to slow PAH progression and reduce the risk of hospitalization in patients with FC II or III symptoms. Its stability and relatively long half-life offer conveniences over conventional prostanoid therapies.

Background: The most plausible hypothesis for takotsubo cardiomyopathy (TCM) is a catecholamine surge. Direct administration of catecholamines or medications causing catecholamine surge is frequently used in clinical practice. Methods: A Medline/PubMed database search was conducted for case reports or series of drug-induced TCM. All reported cases of drug-induced TCM were systemically identified and analyzed. Results: We identified 157 cases of drug-induced TCM. Fifty-seven (36.3%) cases were related to the administration of exogenous catecholamines. In 50 (31.9%) other cases, there was potential adrenergic effect. This included drugs with adrenergic vasoconstriction properties (3.2%), hyperadrenergic state due to alcohol or opioid withdrawal (7.7%), inhibitors of catecholamine reuptake (14.7%), anaphylactic reaction that is accompanied by catecholamine release (3.2%), and psychological or somatic stress coinciding with the administration of a drug that was thought to be the culprit (3.2%). Overall, 68.2% of these drug-induced TCM cases were catecholamine related. In 14 (8.9%) cases, the likely etiology of cardiomyopathy was chemotherapy-induced coronary vasospasm. Conclusion: Our systematic review showed that over two-thirds of drug-induced TCM cases were due to direct or indirect catecholamine stimulation. The lowest effective dose and shortest duration of catecholamines should be utilized, and alternative therapies should be considered if feasible.

Objectives: This study evaluates the impact of carvedilol dose changes on the ventricular arrhythmia event rates for patients ≥ 18 years of age with systolic heart failure and examines dose dependent effects of carvedilol withdrawal in dose reduction and discontinuation subgroups. Methods: This retrospective cohort study included patients with systolic heart failure (EF ≤ 40%) receiving carvedilol. The primary outcome was incidence of ventricular arrhythmia. Ventricular arrhythmia event rates were compared among carvedilol dose continuation, reduction and discontinuation groups. To assess dose dependent effects of beta-blocker withdrawal, dose reduction and discontinuation groups were divided into subgroups. Results: Dose discontinuation (n=64) or reduction group (n=83) had significantly higher ventricular arrhythmia rates compared with dose continuation group (n=262) (65.6 vs 33.7 vs 15.3%, p < 0.001 for both comparisons). Dose discontinuation group also had a significantly higher ventricular arrhythmia event rate compared with dose reduction group (p

NT-pro-BNP is a well-studied biomarker in patients with heart failure not requiring mechanical circulatory support. The propose of the study is to assess the changes in NT-pro-BNP after LVAD implantation. We conducted a retrospective study of patients who had LVAD implantation at the University of