Pharmacotherapy considerations with finerenone in the treatment of chronic kidney disease associated with type 2 diabetes.

PURPOSE: This review provides an overview of the management of chronic kidney disease (CKD) associated with type 2 diabetes (T2D), how the novel treatment class of nonsteroidal mineralocorticoid receptor antagonists (MRAs) fits within the treatment landscape, and how pharmacists can contribute to the multidisciplinary care of patients with CKD associated with T2D. SUMMARY: Optimizing pharmacotherapy for patients with CKD associated with T2D is critical to prevent or slow progression to end-stage kidney disease and reduce the incidence of cardiovascular events. However, many patients with CKD receive suboptimal treatment, in part because of the high complexity of care required, a lack of disease recognition among providers and patients, and a failure to utilize new kidney-protective therapies. Finerenone is the first nonsteroidal, selective MRA to be approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of adult patients with CKD associated with T2D. Clinical trials have demonstrated that finerenone significantly reduces the risk of cardiorenal disease progression vs placebo and has a reduced risk of hyperkalemia compared to traditional steroidal MRAs. Initiation of finerenone should follow evaluation of baseline estimated glomerular filtration rate and serum potassium levels. Consideration of potential drug-drug interactions, follow-up monitoring of potassium levels, and coordination of changes in pharmacotherapy across the patient care team are also important. CONCLUSION: Finerenone is a valuable addition to the treatment landscape for CKD associated with T2D. Through their expertise in -medication -management, transitions of care, and patient education, clinical pharmacists are well positioned to ensure patients receive safe and effective -treatment.

Effect of Replacing Vendor QTc Alerts with a Custom QTc Risk Alert in Inpatients.

OBJECTIVE: The aim of the study is to implement a customized QTc interval clinical decision support (CDS) alert strategy in our electronic health record for hospitalized patients and aimed at providers with the following objectives: minimize QTc prolongation, minimize exposure to QTc prolonging medications, and decrease overall QTc-related alerts. A strategy that was based on the validated QTc risk scoring tool and replacing medication knowledge vendor alerts with custom QTc prolongation alerts was implemented. METHODS: This is a retrospective quasi-experimental study with a pre-intervention period (August 2019 to October 2019) and post-intervention period (December 2019 to February 2020). The custom alert was implemented in November 2019. RESULTS: In the pre-implementation group, 361 (19.3%) patients developed QTc prolongation, and in the post-implementation group, 357 (19.6%) patients developed QTc prolongation (OR: 1.02, 95% CI: 0.87-1.20, p = 0.81). The odds ratio of an action taken post-implementation compared with pre-implementation was 18.90 (95% CI: 14.03-25.47, p <0. 001). There was also a decrease in total orders for QTc prolonging medications from 7,921 (5.5%) to 7,566 (5.3%) with an odds ratio of 0.96 (95% CI: 0.93-0.99, p = 0.01). CONCLUSION: We were able to decrease patient exposure to QTc prolonging medications while not increasing the rate of QTc prolongation as well as improving alert action rate. Additionally, there was a decrease in QTc prolonging medication orders which illustrates the benefit of using a validated risk score with a customized CDS approach compared with a traditional vendor-based strategy. Further research is needed to confirm if an approach implemented at our organization can reduce QTc prolongation rates.

Overview of Riociguat and Its Role in the Treatment of Pulmonary Hypertension.

Pulmonary hypertension (PH), which includes pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), is a progressive condition with significant morbidity and mortality due to right heart failure if left untreated. Riociguat is a soluble guanylate cyclase (sGC) stimulator and is the only treatment approved for both PAH and CTEPH. The objectives of this review are to describe the epidemiology and pathophysiology of PAH and CTEPH; synthesize the pharmacology, efficacy, safety, and utilization of riociguat; and discuss the role of the pharmacist in managing patients with these conditions. Data presented in this review is supported by peer reviewed literature, using PubMed and key words including pulmonary hypertension, pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, and riociguat. The review draws on key studies and review articles that discuss the pathophysiology of PAH and CTEPH, as well as articles discussing the safety and efficacy of riociguat. The overall goal in the treatment of PAH and CTEPH is to improve long-term survival. Treatment planning depends on the type of PH, treatment goals, comorbidities, and risk profiles. Pharmacists serve a valuable role as part of the multidisciplinary team in the care of patients with PH, many of whom may have comorbidities that contribute to high costs and resource utilization. Riociguat is a first-in-class medication and the only approved treatment for both PAH and CTEPH. In clinical trials, riociguat has demonstrated favorable efficacy and tolerability. Riociguat is a valuable addition to the armamentarium of options for treating patients with PH.

Tacrolimus time in therapeutic range and long-term outcomes in heart transplant recipients.

STUDY OBJECTIVE: Little is known about the association between tacrolimus time in therapeutic range (TTR) within the guideline-recommended targets and heart transplant (HT) patient outcomes. This study evaluated the association of early tacrolimus TTR with rejection and other clinical outcomes during an extended follow-up after HT. DESIGN: This was a single-center retrospective cohort study. SETTING: The study was conducted at Michigan Medicine (1/1/2006-12/31/2017). PATIENTS: HT recipients ≥18 years of age were included. MEASUREMENT: The primary end point was the effect of tacrolimus TTR on time to rejection over the entire follow-up period. MAIN RESULTS: A total of 137 patients were included with a median follow-up of 53 months. Based on the median TTR of 58%, the patients were divided into the low tacrolimus TTR (n = 68) and high tacrolimus TTR (n = 69) cohort. The high tacrolimus TTR was associated with a significantly lower risk of rejection compared to the low tacrolimus TTR cohort (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.41-0.98; p = 0.04). A post hoc analysis revealed associations between rejection and TTR when high and low TTR groups were created at different levels. TTR <30% was associated with a 7-fold higher risk of rejection (HR 7.56; 95% CI 1.76-37.6; p < 0.01) and TTR >75% was associated with a 77% lower risk of rejection (HR 0.23; 95% CI 0.08-0.627; p < 0.01). CONCLUSIONS: Patients in the higher tacrolimus TTR cohort had a lower risk of rejection. We observed correlations between higher risk of rejection with TTR <30% and lower risk of rejection with TTR >75%. Future studies should focus on validating the optimal TTR cutoff while also exploring a cutoff to delineate high-risk patients for which early interventions to improve tacrolimus TTR may be beneficial.

Biomarker Trends, Incidence, and Outcomes of Immune Checkpoint Inhibitor-Induced Myocarditis.

Background: Myocarditis is a dreaded and unpredictable complication of immune checkpoint inhibitors (ICI). We sought to determine whether routinely measured biomarkers could be helpful in monitoring for ICI myocarditis. Objectives: The authors examined biomarker trends of patients on ICI and their association with the incidence of ICI myocarditis and outcomes. Methods: We conducted an observational cohort study of adults who received at least one dose of ICI at Michigan Medicine between June 2014 and December 2021 and underwent systematic serial testing for aspartate aminotransferase (AST) and alanine aminotransferase (ALT), creatine phosphokinase (CPK), and lactate dehydrogenase during ICI therapy. Results: Among 2,606 patients (mean age 64 ± 13 years; 60.7% men), 27 (1.0%) were diagnosed with ICI myocarditis. At diagnosis, patients with myocarditis had an elevated high-sensitivity troponin T (100%), ALT (88.9%), AST (85.2%), CPK (88.9%), and lactate dehydrogenase (92.6%). Findings were confirmed in an independent cohort of 30 patients with biopsy-confirmed ICI myocarditis. A total of 95% of patients with ICI myocarditis had elevations in at least 3 biomarkers compared with 5% of patients without myocarditis. Among the noncardiac biomarkers, only CPK was associated (per 100% increase) with the development of myocarditis (HR: 1.83; 95% CI: 1.59-2.10) and all-cause mortality (HR: 1.10; 95% CI: 1.01-1.20) in multivariable analysis. Elevations in CPK had a sensitivity of 99% and specificity of 23% for identifying myocarditis. Conclusions: ICI myocarditis is associated with changes in AST, ALT, and CPK. An increase in noncardiac biomarkers during ICI treatment, notably CPK, should prompt further evaluation for ICI myocarditis.

The Role of sGC Stimulators and Activators in Heart Failure With Reduced Ejection Fraction.

Over the past decade, soluble guanylate cyclase (sGC) activators and stimulators have been developed and studied to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF). The sGC enzyme plays an important role in the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway, that has been largely untargeted by current guideline directed medical therapy (GDMT) for HFrEF. Disruption of the NO-sCG-cGMP pathway can be widely observed in patients with HFrEF leading to endothelial dysfunction. The disruption is caused by an oxidized state resulting in low bioavailability of NO and cGMP. The increase in reactive oxygen species can also result in an oxidized, and subsequently heme free, sGC enzyme that NO is unable to activate, furthering the endothelial dysfunction. The novel sGC stimulators enhance the sensitivity of sGC to NO, and independently stimulate sGC, while the sGC activators target the oxidized and heme free sGC to stimulate cGMP production. This review will discuss the pathophysiologic basis for sGC stimulator and activator use in HFrEF, review the pre-clinical and clinical data, and propose a place in the HFrEF armamentarium for this novel pharmacotherapeutic class.

The real world use of combined P-glycoprotein and moderate CYP3A4 inhibitors with rivaroxaban or apixaban increases bleeding.

The use of direct oral anticoagulants for stroke prevention in atrial fibrillation continues to rise. Certain populations may be at higher risk for increased drug exposure and adverse events. Pharmacokinetic studies suggest increased exposure of rivaroxaban and apixaban with combined P-gp and moderate CYP3A4 inhibitors but the clinical relevance of this is unknown. This retrospective cohort study included patients receiving rivaroxaban or apixaban from January 1, 2012 to December 31, 2016 with a moderate inhibitor (amiodarone, dronedarone, diltiazem, verapamil) for at least 3 months in the drug-drug interaction (DDI) group. Propensity matching was used to identify similar control patients without the presence of the DDI. The primary outcome was a time to event analysis of any bleeding episode as defined by the International Society of Thrombosis and Hemostasis. After propensity matching, 213 patients with similar baseline characteristics were included in each group. The mean CHA2DS2-VASc score was 3.0 and median duration of follow-up was 1.45 years. The primary outcome occurred in 26.4% of patients in the DDI group and 18.4% in the control group (hazard ratio 1.8, 95% confidence interval [CI] 1.19 to 2.73; p-value = 0.006). There was no difference in bleeding rates based on type of inhibitor. Use of a combined P-gp and moderate CYP3A4 inhibitor with rivaroxaban or apixaban increased bleeding risk compared to patients without the DDI in this real world, retrospective study. Analysis in a larger patient population is needed to confirm these findings.

Pulmonary Arterial Hypertension: a Pharmacotherapeutic Update.

PURPOSE OF REVIEW: Pulmonary arterial hypertension (PAH) leads to progressive increases in pulmonary vascular resistance (PVR), right heart failure, and death if left untreated. This review will summarize and discuss recent updates in the classification and management of patients with PAH. RECENT FINDINGS: PAH requires careful hemodynamic assessment and is defined by a mean pulmonary artery pressure > 20 mmHg with normal left-sided filling pressures and a PVR ≥ 3 Wood units. Most patients with PAH require targeted pharmacotherapy based on multiparametric risk stratification. Significant improvements in clinical outcome have been realized through the approval of 14 unique pharmacotherapeutic options. The latest clinical recommendations provide the updated hemodynamic definition and clinical classification as well as evidence-based treatment recommendations. An important change is the focus on initial upfront combination therapy for most patients with PAH. Structured follow-up and escalation of treatment for those not achieving low-risk status is paramount.

Development of best practice recommendations for the safe use of pulmonary hypertension pharmacotherapies using a modified Delphi method.

PURPOSE: The Delphi method was used to develop best practice recommendations (BPR) for safe use of pulmonary hypertension (PH) pharmacotherapies and to describe the pharmacist's role in provision of care. METHODS: A core group reviewed PH medication-safety literature and developed initial BPR. Pharmacists practicing at PH-accredited Centers of Comprehensive Care who met defined PH expert criteria were invited to participate on an expert panel. In round 1 of a 4-round Delphi process, expert input was provided on the BPR. Feedback was incorporated into BPR for the next round. Round 2 proceeded in identical fashion to round 1. In round 3, BPR were deliberated in a teleconference and underwent voting at the cessation of the round using a 5-point Likert scale. Median scores of < 2.5, 2.5-3.75, and > 3.75 resulted in a best practice statement being rejected, reviewed in round 4, or accepted in the final BPR, respectively. In round 4, the remaining BPR were discussed and underwent voting. BPR were assigned a level of evidence and strength of recommendation based on voting results. RESULTS: Eleven PH experts agreed to participate and met expert inclusion criteria, along with 2 pharmacists from the core group, bringing the total number of expert panel members to 13. To guide safe use of PH pharmacotherapies, 26 BPR were developed, categorized into 5 practice domains, comprising the PH Care Center accreditation process, inpatient practice, formulary management, diagnostics, and ambulatory care. BPR included provisions for safe use of parenteral prostacyclin agents and healthcare practitioner education. CONCLUSION: The Delphi method was used to develop BPR to guide safe use of PH pharmacotherapies.

Effects of Total Dose Infusion of Iron Intravenously in Patients With Acute Heart Failure and Anemia (Hemoglobin < 13 g/dl).

Iron deficiency is common in heart failure (HF), and intravenous (IV) iron therapy has been associated with improved clinical status in ambulatory patients with HF. There are limited data to support the safety and efficacy of IV iron administration in patients with acute HF. This was a retrospective cohort study of patients admitted to the University of Michigan Health System for HF with low iron studies during admission. Patients were grouped based on the receipt of IV iron therapy. Study outcomes included change in hemoglobin, 30-day readmission, and adverse events. Forty-four patients who received IV iron and 128 control patients were identified. The mean dose of IV iron received was 1,057 (±336) mg. IV iron resulted in a significantly greater increase in hemoglobin over time (p = 0.0001). The mean change in hemoglobin in the iron and control groups was 0.74 g/dl and 0.01 g/dl at day 7 and 2.61 g/dl and 0.23 g/dl at day 28, respectively. Thirty-day readmission rates were 30% and 22% for patients in the iron and control groups, respectively (p = 0.2787). In conclusion, total dose infusion IV iron is well tolerated and associated with significant improvement in hemoglobin in acute HF.

An Update on the Management of Pulmonary Arterial Hypertension and the Pharmacist's Role.

Pulmonary arterial hypertension (PAH) is a rare medical condition that significantly shortens life expectancy. The lack of understanding and complexity of treatments frequently lead to delays in diagnosis and treatment of patients. This is worsened by the gap in medical education related to the rarity of disease and the subspecialty nature of management. Advancements in diagnostics and treatment in recent years makes a review of this nature important and timely. Understanding the specialty nature of drug therapy, the complexities of managing prostacyclin analogs, and treatment algorithms are essential for pharmacists caring for these patients in both acute and ambulatory settings. This review article will provide an overview of published guidelines as well as discuss new therapies, clinical controversies, and the pharmacist's role in the management of these patients.