Sodium-Glucose Cotransporter-2 Inhibitor and Glucagon-Like Peptide-1 Receptor Agonist Discontinuation in Patients with CKD.

BACKGROUND: Little is known about the association of discontinuation of sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA) with outcomes in patients with chronic kidney disease (CKD). METHODS: We identified adults with CKD stages 3-4 from 2005-2022 in the Veterans Affairs healthcare system. Individuals with an incident prescription for SGLT2 inhibitors or GLP-1 RAs were included, with the first fill date considered the index date. Factors associated with time to first treatment discontinuation, defined as an interruption in SGLT2 inhibitor or GLP-1 RA prescription for ≥90 days, were studied using Cox proportional hazards regression models. Associations of discontinuation 90-179 days and ≥180 days with death, myocardial infarction, coronary revascularization, hospitalization for heart failure, and ischemic stroke were assessed using Cox proportional hazards regression. RESULTS: Of 96,345 individuals who received an SGLT2 inhibitor and 60,020 who received a GLP-1 RA, at least one discontinuation occurred in 35,953 (37%) of SGLT2 inhibitor users and 28,407 (47%) of GLP-1 RA users. SGLT2 inhibitor users were 24% Black, 71% White, 71% age ≥70, and 84% with CKD stage 3a. GLP-1 RA users were 20% Black, 75% White, 63% age ≥70, and 81% with CKD stage 3a. Black race, Hispanic ethnicity, cerebrovascular disease, peripheral vascular disease, and ischemic heart disease were associated with discontinuation of both drug classes. Female sex and more advanced CKD stage were also associated with SGLT2 inhibitor discontinuation. SGLT2 inhibitor discontinuation ≥180 days was associated with death, (adjusted hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.58-1.77) and heart failure hospitalization, (adjusted HR 1.26, 95% CI 1.13-1.40). GLP-1 RA discontinuation ≥180 days was associated with death, (adjusted HR 1.97, 95% CI 1.87-2.07), myocardial infarction (adjusted HR 1.23, 95% CI 1.11-1.36), heart failure hospitalization (adjusted HR 1.48, 95% CI 1.33-1.64), and ischemic stroke (adjusted HR 1.24, 95% CI 1.14-1.35). CONCLUSIONS: SGLT2 inhibitor and GLP-1 RA discontinuation was common and associated with harmful outcomes in adults with CKD.

Understanding Prescribing Practices and Patient Experiences with Renin Angiotensin System Inhibitors Use in Chronic Kidney Disease: A Qualitative Study.

INTRODUCTION: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) improve outcomes but are underutilized in patients with chronic kidney disease (CKD). Little is known about reasons for discontinuation and lack of reinitiating these medications. We aimed to explore clinicians' and patients' experiences and perceptions of ACEI/ARB use in CKD. METHODS: A multi-profession sample of health care clinicians and patients with documented ACEI/ARB-associated side effects in the past 6 months. Participants were recruited from 2 Veterans Affairs healthcare systems in Texas and Tennessee. A total of 15 clinicians and 10 patients completed interviews. We used inductive and deductive qualitative data analysis approaches to identify themes related to clinician and patient experiences with ACEI/ARB. Thematic analysis focused on prescribing decisions and practices, clinical guidelines, and perception of side effects. Data were analyzed as they amassed, and recruitment was stopped at the point of thematic saturation. RESULTS: Clinicians prescribe ACEI/ARB for blood pressure control and kidney protection and underscored the importance of these medications in patients with diabetes. While clinicians described providing comprehensive patient education about ACEI/ARB in CKD, patient interviews revealed significant knowledge gaps about CKD and ACEI/ARB use. Many patients were unaware of their CKD status, and some did not know why they were prescribed ACEI/ARB. Clinicians' drug management strategies varied widely, as did their understanding of prescribing guidelines. They identified structural and patient-level barriers to prescribing and many endorsed the development of a decision support tool to facilitate ACEI/ARB prescribing and management. DISCUSSION/CONCLUSION: Our qualitative study of clinicians and providers identified key target areas for improvement to increase ACEI/ARB utilization in patients with CKD with the goal to improve long-term outcomes in high-risk patients. These findings will also inform the development of a decision support tool to assist with prescribing ACEI/ARBs for patients with CKD.

Fatigue in Patients Receiving Maintenance Hemodialysis: A Review.

Fatigue surrounding hemodialysis treatments is a common and often debilitating symptom that impacts patients' quality of life. Intradialytic fatigue develops or worsens immediately before hemodialysis and persists through the dialysis treatment. Little is known about associated risk factors or pathophysiology, although it may relate to a classic conditioning response. Postdialysis fatigue (PDF) develops or worsens after hemodialysis and may persist for hours. There is no consensus on how to measure PDF. Estimates for the prevalence of PDF range from 20%-86%, likely due to variation in methods of ascertainment and participant characteristics. Several hypotheses seek to explain the pathophysiology of PDF, including inflammation, hypothalamic-pituitary-adrenal axis dysregulation, and osmotic and fluid shifts, but none is currently supported by compelling or consistent data. PDF is associated with several clinical factors, including cardiovascular and hemodynamic effects of the dialysis procedure, laboratory abnormalities, depression, and physical inactivity. Clinical trials have reported hypothesis-generating data about the utility of cold dialysate, frequent dialysis, clearance of large middle molecules, treatment of depression, and exercise as potential treatments. Existing studies are often limited by sample size, lack of a control group, observational design, or short intervention duration. Robust studies are needed to establish the pathophysiology and management of this important symptom.

Documented Adverse Drug Reactions and Discontinuation of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Chronic Kidney Disease.

INTRODUCTION: Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are frequently discontinued in patients with chronic kidney disease (CKD). Documented adverse drug reactions (ADRs) in medical records may provide insight into the reasons for treatment discontinuation. METHODS: In this retrospective cohort of US veterans from 2005 to 2019, we identified individuals with CKD and a current prescription for an ACEi or ARB (current user group) or a discontinued prescription within the preceding 5 years (discontinued group). Documented ADRs in structured datasets associated with an ACEi or ARB were categorized into 17 pre-specified groups. Logistic regression assessed associations of documented ADRs with treatment discontinuation. RESULTS: There were 882,441 (73.0%) individuals in the current user group and 326,794 (27.0%) in the discontinued group. There were 26,434 documented ADRs, with at least one documented ADR in 7,520 (0.9%) current users and 9,569 (2.9%) of the discontinued group. ADR presence was associated with treatment discontinuation, aOR 4.16 (95% CI: 4.03, 4.29). The most common documented ADRs were cough (37.3%), angioedema (14.2%), and allergic reaction (10.4%). ADRs related to angioedema (aOR 3.81, 95% CI: 3.47, 4.17), hyperkalemia (aOR 2.03, 95% CI: 1.84, 2.24), peripheral edema (aOR 1.53, 95% CI: 1.33, 1.77), or acute kidney injury (aOR 1.32, 95% CI: 1.15, 1.51) were associated with treatment discontinuation. CONCLUSION: ADRs leading to drug discontinuation were infrequently documented. ADR types were differentially associated with treatment discontinuation. An understanding of which ADRs lead to treatment discontinuation provides an opportunity to address them at a healthcare system level.

Validation of a predictive model for hospital-acquired acute kidney injury with emergence of SARS-CoV-2 variants.

We previously developed and validated a model to predict acute kidney injury (AKI) in hospitalized coronavirus disease 2019 (COVID-19) patients and found that the variables with the highest importance included a history of chronic kidney disease and markers of inflammation. Here, we assessed model performance during periods when COVID-19 cases were attributable almost exclusively to individual variants. Electronic Health Record data were obtained from patients admitted to 19 hospitals. The outcome was hospital-acquired AKI. The model, previously built in an Inception Cohort, was evaluated in Delta and Omicron cohorts using model discrimination and calibration methods. A total of 9104 patients were included, with 5676 in the Inception Cohort, 2461 in the Delta cohort, and 967 in the Omicron cohort. The Delta Cohort was younger with fewer comorbidities, while Omicron patients had lower rates of intensive care compared with the other cohorts. AKI occurred in 13.7% of the Inception Cohort, compared with 13.8% of Delta and 14.4% of Omicron (Omnibus p = 0.84). Compared with the Inception Cohort (area under the curve (AUC): 0.78, 95% confidence interval (CI): 0.76-0.80), the model showed stable discrimination in the Delta (AUC: 0.78, 95% CI: 0.75-0.80, p = 0.89) and Omicron (AUC: 0.74, 95% CI: 0.70-0.79, p = 0.37) cohorts. Estimated calibration index values were 0.02 (95% CI: 0.01-0.07) for Inception, 0.08 (95% CI: 0.05-0.17) for Delta, and 0.12 (95% CI: 0.04-0.47) for Omicron cohorts, p = 0.10 for both Delta and Omicron vs Inception. Our model for predicting hospital-acquired AKI remained accurate in different COVID-19 variants, suggesting that risk factors for AKI have not substantially evolved across variants.

Predictors, Disparities, and Facility-Level Variation: SGLT2 Inhibitor Prescription Among US Veterans With CKD.

RATIONALE & OBJECTIVE: Sodium/glucose cotransporter 2 (SGLT2) inhibitors are recommended for type 2 diabetes mellitus (T2DM) in patients with chronic kidney disease (CKD) or atherosclerotic cardiovascular disease (ASCVD). We evaluated factors associated with SGLT2 inhibitor prescription, disparities by race and sex, and facility-level variation in prescription patterns. STUDY DESIGN: Retrospective cohort. SETTING & PARTICIPANTS: A national sample of US veterans with comorbid T2DM, CKD, and ASCVD with a primary care visit between January 1 and December 31, 2020. EXPOSURE: Race, sex, and individual Veterans Affairs (VA) location. OUTCOME: SGLT2 inhibitor prescription. ANALYTICAL APPROACH: Multivariable logistic regression assessed associations of race and sex with SGLT2 inhibitor prescription. Facility-level variation in SGLT2i prescription was quantified by median rate ratios (MRR), which express the likelihood that 2 randomly selected facilities differ in their use of SGLT2 inhibitor among similar patients. RESULTS: Of 174,443 patients with CKD, T2DM, and ASCVD, 20,024 (11.5%) were prescribed an SGLT2 inhibitor. Lower odds of SGLT2 inhibitor prescription were seen in Black or African American patients compared with White patients (OR, 0.87 [95% CI, 0.83-0.91]) and among women compared with men (OR, 0.59 [95% CI 0.52-0.67]). The adjusted MRR for SGLT2 inhibitor prescription was 1.58 (95% CI 1.48-1.67) in the total cohort, indicating an unexplained 58% variation in treatment between VA facilities, independent of patient and facility characteristics. Facility-level variation was evaluated among Black or African American patients (MRR, 1.55 [95% CI 1.41-1.68]), White patients (MRR, 1.57 [95% CI 1.47-1.66]), women (MRR, 1.40 [95% CI 1.28-1.51]), and men (MRR, 1.57 [95% CI 1.48-1.67]). LIMITATIONS: Albuminuria was not assessed. CONCLUSIONS: Prescription for SGLT2 inhibitors was low among likely eligible patients, with evident disparities by sex and race and between individual VA facilities. Efforts are needed to study and address the reasons for these disparities to improve equitable adoption of these important medications.

Steroidal or non-steroidal MRAs: should we still enable RAASi use through K binders?

Renin-angiotensin-aldosterone system inhibitors (RAASi) and mineralocorticoid receptor antagonists (MRAs) are important interventions to improve outcomes in patients with chronic kidney disease and heart failure, but their use is limited in some patients by the development of hyperkalemia. The risk of hyperkalemia may differ between agents, with one trial showing lower risk of hyperkalemia with the novel non-steroidal MRA finerenone compared with steroidal MRA spironolactone. Novel potassium binders, including patiromer and sodium zirconium cyclosilicate, are available interventions to manage hyperkalemia and enable continuation of RAASi and MRAs in patients who could benefit from these treatments. These agents bind free potassium ions in the lumen of the gastrointestinal tract to prevent the absorption of dietary potassium and increase potassium secretion. Several studies showed that potassium binders are effective compared with placebo for preventing hyperkalemia or steroidal MRA discontinuation, but none has evaluated whether this strategy impacts clinically important endpoints such as cardiovascular events. Due to this and other limitations related to cost, clinical availability, pill burden and patient selection, alternative potential strategies to mitigate hyperkalemia may be more practical. Conservative strategies include increased monitoring and use of loop or thiazide diuretics to increase urinary potassium excretion. Non-steroidal MRAs may have a lower risk of hyperkalemia than steroidal MRAs and have stronger anti-inflammatory and anti-fibrotic effects with resultant reduced risk of kidney disease progression. Sodium-glucose cotransporter-2 inhibitors also decrease hyperkalemia risk in patients on MRAs and decrease cardiovascular events and kidney disease progression. These may be better first-line interventions to obviate the need for potassium binders and offer additional benefits.

Improving chronic kidney disease detection and treatment in the United States: the chronic kidney disease cascade of care (C3) study protocol.

BACKGROUND: There are major gaps in the implementation of guideline-concordant care for persons with chronic kidney disease (CKD). The CKD Cascade of Care (C3) initiative seeks to improve CKD care by improving detection and treatment of CKD in primary care. METHODS: C3 is a multi-modal initiative deployed in three major academic medical centers within the Department of Veterans Affairs (VA) Health Care System: San Francisco VA, San Diego VA, and Houston VA. The main objective of the first phase of C3 described in this protocol is to establish the infrastructure for universal CKD detection among primary care patients at high-risk for CKD with a triple-marker screen comprising cystatin C, creatinine, and albuminuria. Across the three sites, a comprehensive educational intervention and the integration of primary care-based clinical champions will be employed with the goal of improving CKD detection and treatment. The San Francisco VA will also implement a practice-facilitation intervention leveraging telehealth and health informatics tools and capabilities for enhanced CKD detection. Parallel formative evaluation across the three sites will assess the feasibility and acceptability of integrating cystatin C as part of routine CKD detection in primary care practice. The effectiveness of the interventions will be assessed using a pre-post observational design for change in the proportion of patients tested annually for CKD. Secondary outcomes will assess change in the initiation of cardio-kidney protective therapies and in nephrology referrals of high-risk patients. DISCUSSION: The first phase of C3 is a multi-facility multi-modal initiative that aims to improve CKD care by implementing a triple-marker screen for enhanced CKD detection in primary care.

Heart failure-type symptom scores in chronic kidney disease: The importance of body mass index.

OBJECTIVES: This analysis sought to determine factors (including adiposity-related factors) most associated with HF-type symptoms (fatigue, shortness of breath, and edema) in adults with chronic kidney disease (CKD). BACKGROUND: Symptom burden impairs quality of life in CKD, especially symptoms that overlap with HF. These symptoms are common regardless of clinical HF diagnosis, and may be affected by subtle cardiac dysfunction, kidney dysfunction, and other factors. We used machine learning to investigate cross-sectional relationships of clinical variables with symptom scores in a CKD cohort. METHODS: Participants in the Chronic Renal Insufficiency Cohort (CRIC) with a baseline modified Kansas City Cardiomyopathy Questionnaire (KCCQ) score were included, regardless of prior HF diagnosis. The primary outcome was Overall Summary Score as a continuous measure. Predictors were 99 clinical variables representing demographic, cardiac, kidney and other health dimensions. A correlation filter was applied. Random forest regression models were fitted. Variable importance scores and adjusted predicted outcomes are presented. RESULTS: The cohort included 3426 individuals, 10.3% with prior HF diagnosis. BMI was the most important factor, with BMI 24.3 kg/m2 associated with the least symptoms. Symptoms worsened with higher or lower BMIs, with a potentially clinically relevant 5 point score decline at 35.7 kg/m2 and a 1-point decline at the threshold for low BMI, 18.5 kg/m2. The most important cardiac and kidney factors were heart rate and eGFR, the 4th and 5th most important variables, respectively. Results were similar for secondary analyses. CONCLUSIONS: In a CKD cohort, BMI was the most important feature for explaining HF-type symptoms regardless of clinical HF diagnosis, identifying an important focus for symptom directed investigations.

Natriuretic peptides, extracellular volume, and subclinical cardiovascular changes in chronic kidney disease stages 1-3: a pilot study.

Natriuretic peptide levels are elevated in persons with chronic kidney disease (CKD) stages 1-3, but it remains unclear whether this is associated with extracellular volume excess or early cardiovascular changes. We hypothesized that patients with CKD stages 1-3 would have evidence of cardiovascular changes, which would associate with brain natriuretic peptide (BNP), amino-terminal-pro-BNP (NT-pro-BNP), and patient-reported symptoms.Outpatients with CKD stages 1-3 and non-CKD controls were enrolled. Cardiovascular parameters included extracellular water (ECW) normalized to body weight measured using whole-body multifrequency bioimpedance spectroscopy, and total peripheral resistance index (TPRI) and cardiac index measured by impedance cardiography. Dyspnea, fatigue, depression, and quality of life were quantified using questionnaires.Among 21 participants (13 with CKD), median (IQR) BNP was 47.0 (28.0-302.5) vs 19.0 (12.3-92.3) pg/mL, p=0.07, and NT-pro-BNP was 245.0 (52.0-976.8) vs 26.0 (14.5-225.8) pg/mL, p=0.08, in the CKD and control groups, respectively. Those with CKD had higher pulse pressure (79 (66-87) vs 64 (49-67) mm Hg, p=0.046) and TPRI (3721 (3283-4278) vs 2933 (2745-3198) dyn×s/cm5/m2, p=0.01) and lower cardiac index (2.28 (2.08-2.78) vs 3.08 (2.43-3.37) L/min/m2, p=0.02). In the overall cohort, natriuretic peptides correlated with pulse pressure (BNP r=0.59; NT-pro-BNP r=0.58), cardiac index (BNP r=-0.76; NT-pro-BNP r=-0.62), and TPRI (BNP r=0.48), p<0.05 for each, but not with ECW/weight. TPRI and blood pressure correlated moderately with symptoms.Elevated natriuretic peptides may coincide with low cardiac index and elevated peripheral resistance in patients with CKD stages 1-3. The role of these biomarkers to detect subclinical cardiovascular changes needs to be further explored.

Revisiting diuretic choice in chronic kidney disease.

PURPOSE OF REVIEW: Existing guidelines offer little direction about the use of thiazide and loop diuretics in patients with chronic kidney disease (CKD). This review summarizes recent studies impacting indications and safety considerations for these agents in patients with CKD. RECENT FINDINGS: Chlorthalidone reduces blood pressure compared to placebo in patients with advanced CKD, challenging the belief that thiazide diuretics lose efficacy at lower glomerular filtration rates (GFR). Existing studies show no clear impact of thiazide or loop diuretic use on kidney or cardiovascular outcomes in patients with CKD. Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have diuretic effects, but concomitant use of a diuretic does not diminish the preventive benefits of these agents against acute kidney injury (AKI). Despite theoretical concerns, thiazide diuretics likely do not worsen circulating vasopressin levels or cyst progression in polycystic kidney disease and may be useful for alleviating polyuria from tolvaptan. Diuretics cause multiple adverse effects, including electrolyte abnormalities, hemodynamic-mediated decrease in estimated GFR, and AKI. SUMMARY: Recent evidence supports expanded indications for diuretics in patients with kidney disease, including chlorthalidone for hypertension in advanced CKD. Monitoring electrolytes and estimated GFR is critical to ensure patient safety when prescribing these agents for patients with CKD.

Risk Prediction for Acute Kidney Injury in Patients Hospitalized With COVID-19.

Rationale & Objective: Acute kidney injury (AKI) is common in patients hospitalized with COVID-19, but validated, predictive models for AKI are lacking. We aimed to develop the best predictive model for AKI in hospitalized patients with coronavirus disease 2019 and assess its performance over time with the emergence of vaccines and the Delta variant. Study Design: Longitudinal cohort study. Setting & Participants: Hospitalized patients with a positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction result between March 1, 2020, and August 20, 2021 at 19 hospitals in Texas. Exposures: Comorbid conditions, baseline laboratory data, inflammatory biomarkers. Outcomes: AKI defined by KDIGO (Kidney Disease: Improving Global Outcomes) creatinine criteria. Analytical Approach: Three nested models for AKI were built in a development cohort and validated in 2 out-of-time cohorts. Model discrimination and calibration measures were compared among cohorts to assess performance over time. Results: Of 10,034 patients, 5,676, 2,917, and 1,441 were in the development, validation 1, and validation 2 cohorts, respectively, of whom 776 (13.7%), 368 (12.6%), and 179 (12.4%) developed AKI, respectively (P = 0.26). Patients in the validation cohort 2 had fewer comorbid conditions and were younger than those in the development cohort or validation cohort 1 (mean age, 54 ± 16.8 years vs 61.4 ± 17.5 and 61.7 ± 17.3 years, respectively, P < 0.001). The validation cohort 2 had higher median high-sensitivity C-reactive protein level (81.7 mg/L) versus the development cohort (74.5 mg/L; P < 0.01) and higher median ferritin level (696 ng/mL) versus both the development cohort (444 ng/mL) and validation cohort 1 (496 ng/mL; P < 0.001). The final model, which added high-sensitivity C-reactive protein, ferritin, and D-dimer levels, had an area under the curve of 0.781 (95% CI, 0.763-0.799). Compared with the development cohort, discrimination by area under the curve (validation 1: 0.785 [0.760-0.810], P = 0.79, and validation 2: 0.754 [0.716-0.795], P = 0.53) and calibration by estimated calibration index (validation 1: 0.116 [0.041-0.281], P = 0.11, and validation 2: 0.081 [0.045-0.295], P = 0.11) showed stable performance over time. Limitations: Potential billing and coding bias. Conclusions: We developed and externally validated a model to accurately predict AKI in patients with coronavirus disease 2019. The performance of the model withstood changes in practice patterns and virus variants.

Using dipstick urinalysis to predict development of acute kidney injury in patients with COVID-19.

BACKGROUND: Acute kidney injury (AKI) is a common complication in patients hospitalized with COVID-19 and may require renal replacement therapy (RRT). Dipstick urinalysis is frequently obtained, but data regarding the prognostic value of hematuria and proteinuria for kidney outcomes is scarce. METHODS: Patients with positive severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) PCR, who had a urinalysis obtained on admission to one of 20 hospitals, were included. Nested models with degree of hematuria and proteinuria were used to predict AKI and RRT during admission. Presence of Chronic Kidney Disease (CKD) and baseline serum creatinine were added to test improvement in model fit. RESULTS: Of 5,980 individuals, 829 (13.9%) developed an AKI during admission, and 149 (18.0%) of those with AKI received RRT. Proteinuria and hematuria degrees significantly increased with AKI severity (P < 0.001 for both). Any degree of proteinuria and hematuria was associated with an increased risk of AKI and RRT. In predictive models for AKI, presence of CKD improved the area under the curve (AUC) (95% confidence interval) to 0.73 (0.71, 0.75), P < 0.001, and adding baseline creatinine improved the AUC to 0.85 (0.83, 0.86), P < 0.001, when compared to the base model AUC using only proteinuria and hematuria, AUC = 0.64 (0.62, 0.67). In RRT models, CKD status improved the AUC to 0.78 (0.75, 0.82), P < 0.001, and baseline creatinine improved the AUC to 0.84 (0.80, 0.88), P < 0.001, compared to the base model, AUC = 0.72 (0.68, 0.76). There was no significant improvement in model discrimination when both CKD and baseline serum creatinine were included. CONCLUSIONS: Proteinuria and hematuria values on dipstick urinalysis can be utilized to predict AKI and RRT in hospitalized patients with COVID-19. We derived formulas using these two readily available values to help prognosticate kidney outcomes in these patients. Furthermore, the incorporation of CKD or baseline creatinine increases the accuracy of these formulas.

Correlates of SGLT-2-inhibitiors use among patients with atherosclerotic cardiovascular disease and type 2 diabetes mellitus: Insights from the department of veterans affairs.

This study using data from the Veterans Affairs (VA) administrative and clinical dataset examined determinants of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) use among patients with concomitant atherosclerotic cardiovascular disease (ASCVD) and diabetes mellitus. The aim of the present analysis was to identify barriers and facilitators associated with SGLT-2i in a real-world contemporary patient population in order to improve utilization of these guideline-directed agents.