Exploring Emerging Strategies in the Management of Anemia in Chronic Kidney Disease
A Midday Symposium Conducted at the 2019 ASHP Midyear Clinical Meeting and Exhibition.
Faculty Disclosures
Chair & Presenter Jay B. Wish, MD Professor of Clinical Medicine Chief Medical Officer for Dialysis Indiana University Health Indianapolis, Indiana
Jay B. Wish, MD, has a financial interest/relationship or affiliation in the form of: Consultant and/or Advisor for Akebia Therapeutics; AstraZeneca; Otsuka America Pharmaceutical, Inc.; Rockwell Medical; and Vifor Pharma Management Ltd. Speakers Bureau participant with Akebia Therapeutics and AstraZeneca.
Faculty Disclosures
Presenter Presenter Anil K. Agarwal, MD, FASN Thomas C. Dowling, PharmD, PhD, FCCP Professor of Medicine Professor and Assistant Dean, College of Pharmacy The Ohio State University College of Medicine Director, Office of Research and Sponsored Programs Columbus, Ohio Ferris State University Big Rapids, Michigan Anil K. Agarwal, MD, FASN, has a financial interest/relationship or affiliation in the form of: Thomas C. Dowling, PharmD, PhD, FCCP, has a financial interest/relationship or affiliation in the form of: Consultant and/or Advisor for AstraZeneca and Rockwell Speakers Bureau participant with AstraZeneca. Medical. Grant/Research Support from Akebia Therapeutics. Planning Committee Disclosures
Teresa Haile, RPh, MBA, Lead Pharmacy Planner, MLI, has nothing to disclose.
The planners from Medical Learning Institute, Inc., the accredited provider, and PeerView Institute for Medical Education, the joint provider, do not have any financial relationships with an ACCME-defined commercial interest related to the content of this accredited CPE activity during the past 12 months unless listed below.
Content/Peer Reviewer Disclosures
The following Content/Peer Reviewer(s) have nothing to disclose:
Shelley Chun, PharmD
Disclosure of Unlabeled Use This educational activity may contain discussions of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient's conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.
MasterClass #1 A Closer Look at the Burden of CKD-Associated Anemia and Rationale for HIF-PH Inhibition as a Therapeutic Strategy
Anil K. Agarwal, MD, FASN Professor of Medicine The Ohio State University College of Medicine Columbus, Ohio
Go online to access full [Certification Type] information, including faculty disclosures. Chronic Kidney Disease (CKD) Is Common Among US Adults: Fast Stats1
15% of US adults—37 million people—are estimated to have CKD
Most (9 in 10) adults with CKD do not know they have it
1 in 2 people with very low kidney function who are not on dialysis do not know they have CKD
1. https://www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html. Accessed December 2, 2019. Chronic Kidney Disease (CKD) Is Common Among US Adults: Current Estimates1
CKD is more common in people aged 65 years or older (38%) than in people aged 45 to 64 years (13%) or 18 to 44 years (7%)
CKD is more common in women (15%) than men (12%)
CKD is more common in non-Hispanic blacks (16%) than in non-Hispanic whites (13%) or non-Hispanic Asians (12%)
About 14% of Hispanics have CKD
1. https://www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html. Accessed December 2, 2019. Overview of Anemia in CKD1-3
Anemia remains an important complication experienced by The prevalence of anemia patients with kidney disease, depends on its definition although one that is treatable
When present, it may Anemia generally cause symptoms such increases in frequency as fatigue, weakness, and severity in the more paleness, and advanced stages of CKD shortness of breath and age
1. Fishbane S, Spinowitz B. Am J Kidney Dis. 2018;71:423-435. 2. https://www.niddk.nih.gov/health-information/kidney-disease/anemia. Accessed December 2, 2019. 3. Stauffer ME, Fan T. PLoS One. 2014;9:e84943. Complications Associated With Anemia in CKD1-3
Anemia in CKD is associated with cognitive impairment, sleep disturbances, CKD progression, cardiovascular comorbidities, and higher mortality
Direct healthcare costs are higher in CKD patients with anemia than in those without, and quality of life issues (eg, fatigue, reduced productivity) are common
1. Fishbane S, Spinowitz B. Am J Kidney Dis. 2018;71:423-435. 2. https://www.niddk.nih.gov/health-information/kidney-disease/anemia. Accessed December 2, 2019. 3. Stauffer ME, Fan T. PLoS One. 2014;9:e84943. Flowchart for the Evaluation of the CKD Patient With Anemia1
• CKD 3: at least annually • CKD 4: at least every 6 months • CKD 5 ND: at least every 6 months • CKD 5 PD: at least every 1 month • CKD 5 HD: at least every 1 month No Further Blood loss, CKD Yes hematology hemoglobinopathy, Check Hb workup vitamin B12, folate stages 1-5 No Iron deficiency
Treat with ≤13.0 (men) Yes Yes iron ≤12.0 (women) Workup Normal? Anemia corrected, CBC, RBC indices, periodic follow-ups No iron studies, stool Treat with epoetin, for occult blood Yes if indicated Anemia No workup not corrected
1. Kidney Disease Outcomes Quality Initiative. Am J Kidney Dis. 2006;47:S1-S145. What Are the Potential Harms of ESA Therapy?1
Study Normal Hematocrit Study CHOIR TREAT
ESA, N Epoetin alfa (1,265) Epoetin alfa (1,432) Darbepoetin alfa (4,038) HD patients with coexisting HF or CAD, ND-CKD patients with Hb <11 g/dL ND-CKD patient with T2DM, Population Hct 30% ± 3% on epoetin alfa not previously administered ESA Hb <11 g/dL Hb target, g/dL 14.0 vs 10.0 13.5 vs 11.3 13.0 vs ≥9.0 Median achieved 12.6 vs 10.3 13.0 vs 11.4 12.5 vs 10.6 Hb level, g/dL All-cause mortality, MI, All-cause mortality, MI, Primary endpoint All-cause mortality or nonfatal MI hospitalization for HF, or stroke myocardial ischemia, HF, and stroke
HR or RR (95% CI) 1.28 (1.06-1.56) 1.34 (1.03-1.74) 1.05 (0.94-1.17)
Adverse outcome for All-cause mortality All-cause mortality Stroke higher Hb group HR or RR (95% CI) 1.27 (1.04-1.54) 1.48 (0.97-2.27) 1.92 (1.38-2.68) No difference except less fatigue QOL Better in high Hb group (controversial) No difference in high Hb group ↑ cancer deaths in high Hb group among Comment ↑ VA thrombosis in high Hb group patients with prior history of cancer
1. Epogen (epoetin alfa) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103234s5363s5366lbl.pdf. Accessed December 2, 2019. Balancing Risk vs Benefit of ESA Therapy
Lower target Higher target Hb Hb Balancing Risk vs Benefit of ESA Therapy: A Closer Look at Hb Distribution Impact of PPS (Bundled Payment for Dialysis) and the FDA ESA Label Change (2011)1,2
• Average ESA doses have decreased to around 40% • Mean Hb levels have decreased from 11.5 to 10.8 g/dL (DOPPS) • Observed rates of stroke, VTE, and HF have decreased1 • Transfusion rates have increased from around 2.7% to 3.0% (DOPPS) • Transfusion increase primarily among patients receiving multiple transfusions
Is this an What about acceptable quality of life? trade-off?
1. Chertow GM et al. J Am Soc Nephrol. 2016;27:3129-3138. 2. Hirth RA et al. Am J Kidney Dis. 2014;64:616-621. Quality of Life/Patient-Centered Care in Anemia Management
Although most RCTs have failed to demonstrate any improvement in QOL by raising target Hb from 9-11 g/dL to 13-14 g/dL with ESAs, these are population studies, and there may be individuals who benefit from higher Hb levels
CREATE showed KDIGO acknowledges that some patients TREAT showed a SF-36 improvement may feel better at target Hb levels >11.5 decrease in in all domains at g/dL and recommends that target Hb levels fatigue higher target Hb be individualized for such patients, levels if they are willing to accept the risks Proposed Mechanisms for CV Events at Higher Target Hb Levels and ESA Doses: Which Is Responsible?
Since randomization of the RCTs was by target Hb level, only the target Hb level can be considered cause and effect
Higher ESA doses are highly associated with AEs in secondary analyses
• Patients who achieved higher target Hb levels at low ESA doses had fewer AEs than patients who required high ESA doses to achieve lower target Hb levels • This is highly confounded by comorbidities that may lead to ESA resistance and poorer outcomes Proposed Mechanisms for CV Events at Higher Target Hb Levels and ESA Doses: Other Contributing Factors
Increased blood viscosity because of higher Hb level Improved platelet function at higher Hb levels (more margination) Thrombocytosis because of ESA-induced functional iron deficiency
Hypertension • Increased RBC volume • Decreased peripheral vasodilation at higher Hb levels • Effect of ESAs on vascular smooth muscle (increased endothelin, angiotensin, impaired endothelium-dependent relaxation, and altered calcium homeostasis) Pharmacologic Blood Levels of EPO Have Off-Target Effects1
Peak serum EPO level is 600 mU/mL following IV injection of 30 U/kg EPO; EPO level is 4 to 24 mU/mL in patients with normal Hb levels
At high blood levels, EPO may have paracrine effects on nonerythroid receptors in the heart, brain, CNS, and vasculature, which are cytoprotective but also trophic
Repetitive stimulation and resetting of cardiac growth signals could disorder cardiac modeling, increase vulnerability to stress, or impair the ability of higher Hb levels to diminish left ventricular hypertrophy
1. Fishbane S et al. Clin J Am Soc Nephrol. 2007;2:1274-1282. Clinical Implications of ESA Use
Reproduces deficient native hormone SC administration in non-HD patients
Effective in most patients Long-term cardiovascular events Well tolerated in most patients ESA resistance Thirty years of experience
Does not address IV administration invisible to HD patients iron mobilization disorders What About Iron?
NDD-CKD Hemodialysis
• Iron deficiency is highly prevalent in • Vast majority of patients on HD (80%) patients with NDD-CKD and PD require regular doses of IV iron • KDIGO recommends 1-3 month trial because of ongoing iron losses and of oral iron OR IV iron ESA-accelerated erythropoiesis • Meta-analyses have demonstrated • Because of the inflammatory state of increased efficacy of IV over oral iron ESRD, many patients on HD cannot in raising Hb but no differences adequately mobilize the administered in morbidity or mortality iron and have serum ferritin levels • Oral iron is associated with GI-related that average 800 ng/mL AEs; IV iron is associated with hypotension and allergic reactions Intravenous Iron in CKD: Pros and Cons1
Benefits of IV Iron Risks of IV Iron
• Inflammation • Better bioavailability • Oxidative stress • Rapid efficacy • Cytotoxicity • No compliance issue in • Endothelial dysfunction HD patients • Anaphylaxis • Greater Hb increase • Hemosiderosis • Reduced ESA needs • Bacterial infections • Reduced transfusion needs • Cardiovascular events • Mortality
1. Drüeke TB, Massy ZA. Kidney Int. 2015;88:673-675. Clinical Implications of Supplemental Iron Use
Oral iron often poorly tolerated Addresses iron deficiency and ineffective
IV iron is inconvenient in non-HD CKD patients IV iron easy to administer and usually well tolerated in patients on HD Acute adverse reactions to IV iron
Replaces ongoing iron losses in patients on HD Long-term safety issues (eg, CV toxicity, infection risk, iron overload) Role of Inflammation in the Anemia of CKD Persistent Low-Grade Inflammation Is a Hallmark Feature of CKD1
Renal Cell Injury Inflammation
Increased Decreased Pro-Inflammatory Recruitment of Platelet aggregation Increased ADMA AGE Glutathione cytokines neutrophils and adhesion Decreased fetuin-A β-glucans IL-6 Enhanced coagulation L-fucose IL-8 Esotoxins TNFα Silicone Endothelial Polysaccharides (vascular) injury Oxidation Lipid peroxidation Leptin Inflammation Renal parenchymal damage Iron and endothelial injury Resistin
There is no question that Inflammation contributes to CKD progression, but the link between initiation of the disease and inflammation is still debated2
1. Silverstein DM et al. Pediatr Nephrol 2009;24:1445-1452. 2. Mihai S et al. J Immunol Res 2018;2018:2180373. Over 50% of Patients With CKD Have Evidence of Active Inflammation
Predicted prevalence of C-reactive protein among DistributionDistribution of inflammationof inflammation score score by categories by categories 1 2 2
patients with CKD (NHANES III, N = 15, 594) of eGFR (CRICof eGFR study, (CRIC N = study,3,993) N = 3,993)
0 2 2 11 6 100 100 7 28
C-reactive protein C-reactive protein 100% 24 47 62
>0.21 mg/dL >1 mg/dL 50 107 95% confidence 187 200 81% 95% confidence 171 80%80 100 69% 232 score Inflammation
357 5 55% 60%60 336 283 4 50 43% 42% 44% 38% 127 3 38% 36% Percent 2 36% 40%40 229 304 1 23% 14% 258 0 14% 11% 116 180 10% 9% 20%20
Proportion of Population, % Population, of Proportion 114 137 94 50 0 0%0 15 30 60 90 120 >60 50-59 40-49 30-39 <30 eGFR, mL/min/1.73 m2 eGFR, mL/min/1.73 m2
1. Eustace JA et al. Kidney Int. 2004;65:1031-1040. 2. Gupta J et al. Clin J Am Soc Nephrol. 2012;7:1938-1946. Hepcidin Controls Extracellular Iron Concentration and Iron Storage
1. Steinbicker AU. Nutrients 2013;5:3034-3061. 2. Babitt JL et al. J Am Soc Nephrol. 2012;23:1631-1634. 3. D'Angelo G. Blood Res 2013;48:10-15. Hepcidin Functions Via Effects on Ferroportin-Mediated Iron Efflux1 Low Hepcidin High Hepcidin
• Hepcidin binds to and results in Iron uptake Iron uptake the internalization and degradation of ferroportin • This leads to a block in iron efflux from ferroportin-expressing cells ‒ In low hepcidin states, iron Ferritin Ferritin taken up by these cells is exported via ferroportin Fpn ‒ In high hepcidin states, the loss of membrane ferroportin results in iron sequestration Fpn Iron release into plasma Hepcidin Fe Fe 1. Ginzburg YZ. Vitam Horm 2019;110:17-45. Hepcidin Production Is Increased in CKD and Inflammation1
Association between hepcidin levels and kidney function or inflammation Prospective hospital-based cohort study in patients with CKD stages 1-5 conducted between January 2000 and January 2012 (N = 1,095) P = .0002 60 60 56.4
50 50
P = .02 40 36.1 40
30 30 26.7 23.3
20 20 Hepcidin, Hepcidin, ng/mL Hepcidin, Hepcidin, ng/mL 10 10
0 0 mGFR mGFR CRP ≤8 mg/L CRP >8 mg/L ≥60 mL/min/1.73 m2 <15 mL/min/1.73 m2 1. Mercadel L et al. PLoS ONE 2014;9:e99781. Hepcidin is Associated with Low Hemoglobin
Association between hepcidin and Hb1 Cross-sectional study in patients with NDD-CKD (N = 505)
1. Uehata T et al. Nephrol Dial Transplant. 2012;27:1076-1083. There Is a Difference Between Absolute and Functional Iron Deficiency1
• Absolute: severely reduced or absent iron stores in bone marrow, liver, and spleen • Functional: normal or increased total body iron; unavailable for incorporation into erythroid precursors – Mainly because of increased hepcidin, which inhibits iron mobilization from intracellular stores
Absolute Functional Normal iron deficiency iron deficiency Storage iron Transport iron Erythron iron
1. Gafter-Gvili A et al. Acta Haematol. 2019;142:44-50. Functional Iron Deficiency Is Prevalent in Patients With CKD
1. Koury M et al. Nat Rev Nephrol 2015;11:394-410. 2. Wish JB. Clin J Am Soc Nephrol. 2006;1:S4-8. 3. Anand IS et al. Circulation 2018;138:80-98. Iron Deficiency Is a Major Cause of ESA Hyporesponsivness1
Up to 10% of patients with CKD Over 30% of patients treated with experience hyporesponsiveness to ESAs fail to achieve Hb ≥11 g/dL and ESA therapy >50% have inadequate iron statusa 60 51
50
40 34 30
Patients,% 20
10
0
Low response Normal response Fail to achieve ≥11 g/dL Inadequate iron status a Defined as a serum ferritin concentration <100 mg/L and/or a TSAT <20% (or a hypochromic red cell value of >10%). 1. Johnson DW et al. Nephrology (Carlton). 2007;12:321-330. Inflammation Limits Utilization of Exogenous Iron Needing High ESA Doses1
TSAT, epoetin alfa dose requirements, and Hb levels at different stages of inflammation Retrospective cohort study of patients on HD ≥18 years of age between July 1, 2000, and June 30, 2002, who had no history of PD (N = 1,754)
29.6 28.5 25.4 TSAT (%) 22.7
Epoetin alfa dose 11.6 11.6 11.3 11.3 10.8 (kU/administration) 7.3 7.4 8.4 Hb (g/dL)
CRP level: <1.3 g/dL 1.3-2.04 g/dL 2.04-3.21 g/dL >3.21 g/dL
1. Bradbury BD et al. Nephrol Dial Transplant. 2009;24:919-925. Summary and Conclusions
• CKD anemia is multifactorial – Primarily because of EPO insufficiency, iron deficiency (absolute or functional), and inflammation • Current paradigm of supplementing ESA and iron without addressing inflammation is fraught with consequences – Demonstrated in RCTs • New methods of treating anemia are needed to address this MasterClass #2 Expert Insight on the Clinical Potential of HIF-PH Inhibitors in CKD-Associated Anemia
Jay B. Wish, MD Professor of Clinical Medicine Chief Medical Officer for Dialysis Indiana University Health Indianapolis, Indiana
Go online to access full [Certification Type] information, including faculty disclosures. Oxygen Sensing and the Anemia of CKD The Etiology of Anemia in CKD Is 1-4 Kathryn: is EPO in Multifactorial in Nature figure erythropoietin?
Factors that contribute to anemia in CKD include ↓EPO • Dysregulation of renal hypoxic response ↑ • Reduction of erythropoietin production • Chronic inflammation • Uremic toxins ↓ • Iron deficiency (absolute) • Blood loss • Shortened RBC life span
• Increased hepcidin levels, leading to ↓ functional iron deficiency
1. Brugnara C et al. In: Skorecki K et al, eds. Brenner & Rector’s the Kidney. 10th ed. Philadelphia, PA: Elsevier; 2016:1875-1911. 2. Babitt JL, Lin HY. J Am Soc Nephrol. 2012;23:1631-1634. 3. Ly J et al. Am J Kidney Dis. 2004;44:715-719. 4. Koury MJ, Haase VH. Nat Rev Nephrol. 2015;11:394-410. The Kidney Acts as an Oxygen Sensor to Regulate RBC Production1,2 Kathryn: is EPO here erythropoietin? • EPO is a hematopoietic growth factor produced primarily in the kidney • Healthy kidneys adapt to sensed changes in oxygen content, either because of inspiratory hypoxia or anemia, by increasing the number of renal erythropoietin-producing and oxygen-sensing (REPOS) cells in the juxtamedullary cortex • REPOS cells account for ~90% of total erythropoietin synthesis
1. Donnelly S. Am J Kidney Dis. 2001;38:415-425. 2. Wenger RH, Hoogewijs D. Am J Physiol Renal Physiol. 2010;298:F1287-F1296. Factors That Impact Balance of Renal Oxygen Supply and Demand Alter Renal-Tissue Oxygen Levels1
• Primary factor responsible for renal oxygen consumption is sodium reabsorption ─ Sodium reabsorption is primarily determined by the GFR • GFR is proportional to and determined by renal blood flow
1. Donnelly S. Am J Kidney Dis. 2001;38:415-425. Sensed Changes in Renal Tissue Oxygen Levels Regulate Erythropoietin Production1-3
• Rate of RBC production is Kathryn: is EPO in figure erythropoietin? adjusted by regulation of Also, in top label in erythropoietin production in figure, it says both. kidney to meet oxygen demand of peripheral tissues • Hypoxia stimulates new RBC production through increased production of erythropoietin
primarily in kidneys ↑ • Erythropoietin acts on cell ↑ surface receptors in bone marrow to stimulate erythropoiesis
1. Fishbane S, Spinowitz B. Am J Kidney Dis. 2018;71:423-435. 2. Haase VH. Blood Rev. 2013;27:41-53. 3. Adapted from: Jelkmann W. J Physiol. 2011;589(Pt 6):1251-1258. Iron Homeostasis Is Essential for Effective Hematopoiesis1,2
Senescent RBC
• Iron homeostasis is controlled by a regulatory network involving four main components ─ Bone marrow erythropoiesis ─ Tissue oxygen delivery ─ Iron stores ─ Inflammation
1. Ganz T. Best Pract Res Clin Haematol. 2005;18:171-182. 2. Babitt JL, Lin HY. J Am Soc Nephrol. 2012;23:1631-1634. Iron Homeostasis Is Essential for Effective Hematopoiesis1,2
Senescent RBC
• Hepcidin is a peptide produced by liver to regulate absorption and mobilization • Hepcidin acts to decrease serum iron levels by blocking ─ Iron absorption from the intestine ─ Iron recycling from macrophages ─ Mobilization of stored iron
1. Ganz T. Best Pract Res Clin Haematol. 2005;18:171-182. 2. Babitt JL, Lin HY. J Am Soc Nephrol. 2012;23:1631-1634. REPOS Cells in Kidney Continuously Sense Oxygen Levels and Regulate Activity of HIF Accordingly1,2
Kathryn: is EPO in • REPOS cells are peritubular, figure erythropoietin? interstitial, fibroblast-like cells • Oxygenation of REPOS cells depends largely on the regional blood oxygen levels • Activity of HIF, a key transcription factor that induces expression of erythropoietin and other genes, in the REPOS cells produces a physiologic response to changes in oxygen levels
1. Haase VH. Blood Rev. 2013;27:41-53. 2. Wenger RH, Hoogewijs D. Am J Physiol Renal Physiol. 2010;298:F1287-F1296. HIFs Mediate Responses to Sensed Changes in Tissue Oxygen Levels1,2
• HIF is a transcription factor composed of an α and β subunit
• HIF-β is present continually, but HIF-α levels vary depending on ambient oxygen levels • Prolyl-hydroxylase domain (PHD) enzymes continuously “sense” oxygen levels • When oxygen levels are normal, PHD enzymes hydroxylate HIF-α; once hydroxylated, reacts with von Hippel- Lindau (VHL) protein and is ultimately degraded
1. West JB. N Engl J Med. 2017;376:1965-1971. 2. Wenger RH, Hoogewijs D. Am J Physiol Renal Physiol. 2010;298:F1287-F1296. HIFs Coordinate a Series of Responses to Hypoxia and Regulate Erythropoiesis1
• In hypoxic conditions, the PHD enzyme cannot hydroxylate HIF-α, preventing HIF-α from binding to VHL protein, thus allowing HIF-α to persist intact • HIF-α then translocates to cell nucleus, binds with a HIF-β subunit to become functionally active, resulting in upregulation and downregulation of target genes that mediate adaptive physiologic responses, such as increased erythropoiesis
1. West JB. N Engl J Med. 2017;376:1965-1971. Activation of HIF Pathway Synchronizes Increased EPO Production With Upregulation of Iron Absorption1-4 Kathryn: is EPO here erythropoietin? Also in figure?
1. Dev S, Babitt JL. Hemodial Int. 2017;21:S6-S20. 2. Koury MJ, Haase VH. Nat Rev Nephrol. 2015;11:394-410. 3. Coyne DW et al. Kidney Int Suppl (2011). 2017;7:157-163. 4. Gupta N, Wish JB. Am J Kidney Dis. 2017;69:815-826. Overview of Erythropoietic Effects of HIF Activation1
1. HIF upregulates DMT1 and DcytB to increase intestinal Fe absorption Kathryn: is EPO in 2. Transferrin transports Fe to transferrin receptors in the bone figure erythropoietin? marrow 3. Fe released from transferrin into developing erythrocyte 4. HIF upregulates the EPO receptor and endogenous EPO Kathryn: is EPO here production erythropoietin? 5. HIF downregulates hepcidin receptor expression in hepatocytes 6. HIF upregulates transferrin receptor, increasing iron uptake by proerythrocytes 7. HIF promotes the formation of fully functional mature erythrocytes replete with Hb 8. After a lifespan averaging approximately 120 days, exhausted erythrocytes are scavenged in liver and Fe is returned for reuse
1. Gupta N, Wish JB. Am J Kidney Dis. 2017;69:815-826. Dysregulation of the Kidney’s Hypoxic Response in CKD Anemia1-3
Dysregulation of the renal hypoxic response develops as a result of Kathryn: is EPO in • Impaired renal oxygen figure erythropoietin? sensing • Reduced number of REPOS cells available to elicit a hypoxic response
1. Brugnara C et al. In: Skorecki K et al, eds. Brenner & Rector’s the Kidney. 10th ed. Philadelphia, PA: Elsevier; 2016:1875-1911. 2. Wenger RH, Hoogewijs D. Am J Physiol Renal Physiol. 2010;298:F1287-F1296. 3. Adapted from Besarab A et al. In: Provenzano R et al. eds. Management of Anemia. New York., NY. Springer Science and Business Media; 2018:11-29. CKD Disrupts the Oxygen-Sensing Mechanism in the Kidney1-5
• As GFR declines, sodium reabsorption Impaired Oxygen-Sensing Mechanism decreases in tandem Senses Pseudonormoxia in the Kidney • As sodium reabsorption decreases, renal oxygen demand decreases leading to
increased intra-renal oxygen tension (pO2) • Impaired kidney perceives sufficient oxygen, a “pseudonormoxic” state, and fails to activate HIF pathway • Impaired kidney oxygen sensor no longer Kathryn: is EPO here responds appropriately to body’s oxygen erythropoietin? needs, contributing to decline in EPO production
1. Brugnara C et al. In: Skorecki K et al, eds. Brenner & Rector’s the Kidney. 10th ed. Philadelphia, PA: Elsevier; 2016:1875-1911. 2. Locatelli F et al. Am J Nephrol. 2017;45:187-199. 3. Wenger RH, Hoogewijs D. Am J Physiol Renal Physiol. 2010;298:F1287-1296. 4. Donnelly S. Am J Kidney Dis. 2001;38:415-425. 5. Halperin ML et al. Clin J Am Soc Nephrol. 2006;1:1049-1053. Disruption of the Oxygen-Sensing Mechanism Prevents HIF Pathway Activation1-3
Kathryn: is EPO in figure erythropoietin? Impaired oxygen-sensing Kathryn: is EPO here mechanism prevents HIF activation, erythropoietin? resulting in insufficient levels of • Endogenous EPO production • Iron absorption and delivery to bone marrow • Erythropoiesis
1. Bernhardt WM et al. Proc Natl Acad Sci U S A. 2009;106:21276-21281. 2. Brugnara C et al. In: Skorecki K et al, eds. Brenner & Rector’s the Kidney. 10th ed. Philadelphia, PA: Elsevier; 2016:1875-1911. 3. Liu Q et al. J Clin Invest. 2012;122:4635-4644. Reduction in REPOS Cells in CKD Renders Patients Unable to Produce an Adequate EPO Response to Hypoxic Stimuli1,2
Kathryn: is EPO in figure erythropoietin?
Also in title and text box?
In CKD, REPOS cells convert into collagen-producing myofibroblasts, resulting in reduced renal EPO output and the development of anemia • Under conditions of severe hypoxia or in patients with advanced CKD, the liver contributes to plasma EPO levels
1. Haase VH. Blood Rev. 2013;27:41-53. 2. Koury MJ, Haase VH. Nat Rev Nephrol. 2015;11:394-410. HIF Stabilizers Currently in Development1
Compound Development Status Enzyme Inhibition
FG-4592 (Roxadustat) Phase 31 HIF-PHD 1, HIF-PHD 2, and HIF-PHD 3
AKB-6548 (Vadadustat) Phase 31 Not specified
GSK1278863 (Daprodustat) Phase 31 HIF-PHD 2 and HIF-PHD 3
BAY85-3934 (Molidustat) Phase 32 HIF-PHD 2
JTZ-951 (Enarodustat) Phase 33 Not specified
Desidustat Phase 34 Not specified
JNJ-42905343 Preclinical1 Not specified
1. Locatelli F, et al. Am J Nephrol 2017;45:187-199. 2. https://clinicaltrials.gov/ct2/show/NCT03350347. Accessed December 3, 2019. 3. https://rctportal.niph.go.jp/en/detail?trial_id=JapicCTI-183870. Accessed December 3, 2019. 4. https://zyduscadila.com/public/pdf/pressrelease/Press- Release-Phase-3-Trial-of-Desidustat-in-Chronic-Kidney-Disease.pdf. Accessed December 3, 2019. HIF Stabilizers in Development in the United States
Roxadustat Vadadustat Daprodustat
Half-Life 12-13 hours 4.5 hours 4 hours
Daily or 3 times Dosing Frequency 3 times weekly Daily weekly (double daily dose)
HIF-α HIF-1α and HIF-1α and HIF-2α > HIF-1α Stabilization HIF-2α HIF-2α
HIF-PHD 1, HIF-PHD 3 > HIF-PHD 2 Enzyme Inhibition HIF-PHD 2, and HIF-PHD 2 and HIF-PHD 3 HIF-PHD 3 Treatment With Roxadustat1,2
1. Chen N et al. N Engl J Med. 2019;381:1011-1022. 2. Chen N et al. N Engl J Med. 2019;381:1001-1010. Roxadustat Chinese Studies
• Efficacy superiority to placebo in NDD-CKD patients
• Efficacy noninferiority to ESA in HD patients
• Not adequately powered for MACE outcomes (<1,000 patients, 6 months duration)
• Increased hyperkalemia in NDD-CKD patients on active drug
• No other safety signals noted
• Roxadustat equally effective in patients with high or low CRP in HD study Chinese Patients Undergoing Dialysis: Mean Doses of Roxadustat and Epoetin Alfa and Hb Levels Over Time1
Roxadustat Epoetin Alfa 12.5 12.5
12.0 Baseline CRP >ULN (N = 45) 12.0
11.5 11.5 Baseline CRP ≤ULN (N = 78)
11.0 Baseline CRP ≤ULN (N = 151) 11.0
10.5 10.5 Mean Hb, g/dL Hb, Mean Mean Hb, g/dL Hb, Mean 10.0 10.0 Baseline CRP >ULN (N = 20) 9.5 9.5
0.0 0.0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 1 3 5 7 9 11 13 15 17 19 21 23 25 27 Trial Week Trial Week Baseline CRP ≤ULN Baseline CRP >ULN Baseline CRP ≤ULN Baseline CRP >ULN 6 12,000 (N = 151) (N = 45) (N = 78) (N = 20)
5 10,000
4 8,000
3 6,000 IU
mg/kg 2 4,000
1 2,000
0 0
Mean Weekly Roxadustat Dose, Dose, Roxadustat Weekly Mean Mean Weekly Epoetin Alfa Dose, Alfa Epoetin Weekly Mean 1 3 5 7 9 11 13 15 17 19 21 23 25 27 1 3 5 7 9 11 13 15 17 19 21 23 25 27 Trial Week Trial Week 1. Chen N et al. N Engl J Med. 2019 ;381:1011-1022. Cardiovascular Safety of Roxadustat Was Confirmed in Pooled Analyses1
Population, All-Cause MACE MACE+ Conclusion Comparator Mortality
HR = 1.08 HR = 1.04 HR = 1.06 Risk of MACE, MACE+, and all-cause NDD (95% CI, (95% CI, (95% CI, mortality in roxadustat patients (n = 4,270) placebo 0.94-1.24) 0.91-1.18) 0.91-1.23) comparable with placebo
Those taking roxadustat had 30% ↓ risk HR = 0.70 HR = 0.66 HR = 0.76 of MACE and 34% ↓ risk of MACE+ ID (95% CI, (95% CI, (95% CI, compared with those taking EPO, with a (n = 1,526) EPO 0.51-0.96) 0.50-0.89) 0.52-1.11) trend toward ↓ all-cause mortality for roxadustat, relative to EPO
HR = 0.96 HR = 0.86 HR = 0.96 No ↑ risk of MACE and all-cause DD (95% CI, (95% CI, (95% CI, mortality and a ↓ risk of MACE+ (n = 3,880) EPO 0.82-1.13) 0.74-0.98) 0.79-1.17) compared with EPO
1. Provenzano R et al. American Society of Nephrology Kidney Week 2019 (ASN 2019). Abstract FR-OR131. Other Benefits of Roxadustat in Pooled Analyses of Kathryn: there Phase 3 Global Studies is so much text here. Can Slower eGFR decline observed in NDD patients we get rid of • In patients with baseline eGFR ≥15 mL/min/1.73 m2, with a treatment difference of 1.62 mL/min/1.73 m2 in some? eGFR change at 12 months from the baseline (P < .0001), or a reduction by 38% in eGFR decline in the roxadustat arm relative to the placebo arm Improvements in quality of life measures in NDD patients • Statistically significant improvements from baseline to week 12 in quality of life endpoints, including SF-36 vitality subscale (P = .0002), SF-36 physical functioning subscale (P = .0369), FACT-AN anemia subscale (P = .0012), FACT-AN total score (P = .0056), and EQ-5D-SL VAS score (P = .0005) when comparing roxadustat with placebo in CKD patients not on dialysis Efficacy regardless of inflammation status • Mean achieved Hb levels and roxadustat dose requirements were not impacted by baseline CRP levels in multiple phase 3 studies, including in SIERRAS study, which is reflective of US dialysis practice under current ESA labeling restrictions – in SIERRAS, roxadustat dose requirements remained stable over time, while epoetin alfa dose requirements increased by 57% over 52 weeks in the epoetin alfa arm Summary of Roxadustat Global Phase 3 Studies1-6
DD-CKD Studies Population, Comparator Results Kathryn: all EPOs here are epoetin HIMALAYAS N = 1,043, incident dialysis vs EPO Superior to EPO alfa? SIERRAS N = 741, stable dialysis vs EPO Superior to EPO ROCKIES N = 2,133, stable/incident dialysis vs EPO Superior to EPO PYRENEES N = 836, stable dialysis vs EPO or darbepoetin Superior to ESA NDD-CKD Studies Population, Comparator Results ALPS N = 594, nondialysis vs placebo Superior to placebo ANDES N = 922, nondialysis vs placebo Superior to placebo OLYMPUS N = 2,781, nondialysis vs placebo Superior to placebo
1. Provenzano R al. ASN 2019. Abstract TH-OR021. 2. Charytan C et al. ASN 2019. Abstract SA-PO227. 3. Fishbane S et al. ASN 2019. Abstract TH-OR022. 4. Esposito C et al. ASN 2019. Abstract SA-PO225. 5. Coyne D et al. ASN 2019. Abstract SA-PO228. 6. Fishbane S et al. ASN 2019. Abstract TH-OR023. Vadadustat in Patients With Anemia Because of CKD1-3
• 304 NDD pts, duration 52 wk; vadadustat vs darbepoetin – Noninferior for efficacy; no difference in AEs or SAEs
• 323 HD pts already receiving darbepoetin, converted to vadadustat or continued on darbepoetin for 52 wk – Noninferior for efficacy; no difference in AEs or SAEs
• Open label study of vadadustat in 42 PD pts, duration 24 wk; met efficacy target for increase in Hb – 28.6% incidence of SAE, including one fatal MI attributed to study drug
• Open label study in vadadustat in 24 ESA-naïve HD pts, for 25 wk; met efficacy target for increase in Hb – 29.2% incidence of SAE, none attributed to study drug
1. Nangaku M et al. ASN 2019. Abstract SA-PO229. 2. Nangaku M et al. ASN 2019. Abstract TH-OR024. 3. https://www.businesswire.com/news/home/20190312005287/en/. Accessed December 5, 2019. Vadadustat: Ongoing Phase 3 Trials1
INNO2VATE-CORRECTION/ CONVERSION • Vadadustat vs darbepoetin alfa in incident DD patients (N = 369)
INNO2VATE-CONVERSION • Vadadustat vs darbepoetin alfa in ESA-treated DD patients (N = 3,554)
PRO2TECT-CORRECTION • Vadadustat vs darbepoetin alfa in NDD patients Kathryn: Should (N = 1,761) we give the specific pages PRO2TECT-CONVERSION • Vadadustat vs darbepoetin alfa in ESA-treated NDD patients for the refs and (N = 1,752) not the general URL? 1. https://clinicaltrials.gov/. Accessed November 21, 2019. Daprodustat in Patients With Anemia Because of CKD1-3
• 271 HD pts, duration 52 wk; daprodustat vs darbepoetin – Noninferior for efficacy; no difference in AEs or SAEs
• 299 NDD pts, duration 52 wk; daprodustat vs epoetin beta pegol – Noninferior for efficacy; no difference in AEs or SAEs
• Open label study of daprodustat in 28 HD pts, duration 24 wk; met efficacy target for increase in Hb – 10.7% incidence of SAE, including three shunt occlusions and one device dislocation
1. https://academic.oup.com/ndt/article/34/Supplement_1/gfz101.SaO036/5515669. Accessed December 5, 2019. 2. http://mediatheque.cyim.com/mediatheque/media.aspx?mediaId=70761&channel=60398. Accessed November 21, 2019. 3. https://www.clinicaltrials.gov/ct2/show/results/NCT02829320?term=daprodustat&draw=2&rank=14. Accessed November 21, 2019 Daprodustat: Ongoing Phase 3 Trials1
ASCEND-ID • Daprodustat vs darbepoetin alfa in ID patients (N = 300)
ASCEND-TD • Daprodustat administered three times weekly vs epoetin alfa (N = 407)
ASCEND-NHQ • Daprodustat vs placebo in NDD patients (N = 600) Kathryn: Should ASCEND-D • Daprodustat vs rhEPO in HD patients switching from an ESA we give the (N = 2,698) specific pages for the refs and ASCEND-ND • Daprodustat vs darbepoetin alfa in NDD patients; will include not the general (N = 4,500) patients either switching from or naïve to an ESA URL? 1. https://clinicaltrials.gov/. Accessed November 21, 2019. Other Beneficial Effects of HIF Stabilizers From Phase 2 Studies
• Reduction in cholesterol • Reduction in hepcidin • Reduction in blood pressure Roxadustat and Cholesterol1
Roxadustat Lowers Total Cholesterol in Dialysis Patients
1. Provenzano R et al. Am J Kidney Dis. 2016;67:912-924. Roxadustat and Daprodustat: Effects on Hepcidin
1. Provenzano R et al. Am J Kidney Dis. 2016;67:912-924. 2. Brigandi RA et al. Am J Kidney Dis. 2016;67:861-871. Roxadustat Decreases Blood Pressure in a Phase 2a Study1
94
92
90
88
mmHg 86
84
Mean Arterial Pressure, ArterialPressure, Mean 82
80 Baseline End of Treatment 4 Weeks After Treatment (n = 48) (n = 48) (n = 42)
Patients who had received FG-4592 within 5 days prior to blood pressure assessment, had not interrupted or discontinued treatment, and had not had any changes in blood pressure medication were included in the analysis. Baseline is the mean of all available pretreatment measurements; end of treatment was weeks 16/17 for cohorts A and B, and weeks 24/25 for cohorts C and D
1. Beserab A et al. ASN 2011. Abstract TH-PO364. HIF-PH Inhibitors: Safety Concerns
Potential upregulation of several hundred other hypoxia sensitive genes, including those involved in
• Glucose regulation • Angiogenesis • Extracellular matrix production • Cell proliferation and survival
Elevation of liver enzymes
Fatal hepatic necrosis occurred in patient in FG-2216 trial; not attributed to the drug, but none since with other PHIs HIF-PH Inhibitors: Safety Concerns
No increase in BP so far; in fact, some BP lowering similar to enalapril in clinical studies
Possible association of HIF-2 with pulmonary hypertension—remains to be seen
No increase in VEGF levels in doses used
Small doses and short duration of phase 2 and even phase 3 clinical trials are insufficient to predict all possible side effects HIF Stabilizers: The Value Proposition
Calculating a value proposition at the present time is difficult
For 2 years after their approval, HIF-stabilizers will be outside the dialysis bundle based on TDAPA
Since the HIF-stabilizers seem to work better than ESAs in inflamed patients, that will probably be first HD group in whom they are embraced HIF Stabilizers: The Value Proposition (Cont’d)
Roxadustat studies that demonstrate safety superiority to ESAs in ID patients makes that second HD group in which HIF-stabilizers are likely to be embraced
Likely that dialysis patients with ESA dose requirements below average (cost < allowance in bundle) will stay on ESAs
Oral route of administration of HIF stabilizers makes them more attractive than ESAs in NDD-CKD and PD patients Summary and Conclusions
• HIF stabilizers are first revolutionary treatment for anemia of CKD since ESAs were introduced 30 years ago • HIF stabilizers may replace ESAs in NDD-CKD patients because – They are orally administered – They are no less safe than placebo (and not likely to carry a black box warning) – They may be ordered by non-nephrologists (PCPs, endo, cardio) • HIF stabilizers will replace ESAs in ESA-resistant, inflamed HD patients who may have better outcomes because of lower ESA doses and higher Hb levels • Value proposition of HIF-stabilizers in prevalent HD population remains to be seen because of unknown costs of agents and effects of TDAPA • Long-term safety of HIF-stabilizers (non-MACE/MACE+), such as angiogenesis, extracellular matrix production, and pulmonary hypertension, may remain unknown for many years Practicum Defining the Role of Pharmacists in the Evolving Treatment Landscape for Anemia in CKD
Thomas C. Dowling, PharmD, PhD, FCCP Professor and Assistant Dean, College of Pharmacy Director, Office of Research and Sponsored Programs Ferris State University Big Rapids, Michigan
Go online to access full [Certification Type] information, including faculty disclosures.
Objectives
1. Describe the critical 2. Discuss key 3. Discuss cases that role of pharmacists components of a demonstrate how in the management collaborative pharmacists may of CKD-related practice agreement integrate emerging anemia for anemia therapies for the management treatment of CKD- related anemia into existing treatment regimens Review of Pharmacist-Managed CKD Clinics1
International systematic review of pharmacists’ interventions in CKD; included 37 studies with 4,743 patients
Of the eight controlled studies, including 744 CKD patients, pharmacist interventions were associated with • Reduced composite of ESRD and mortality in diabetics 14.8 vs 28.2 per 100 patient-years (P < .001; adjusted relative risk 60%) • Reduced all-cause hospitalizations: 1.8 ± 2.4 vs 3.1 ± 3.0 (P = .02) • Improved anemia management (target hemoglobin; P = .0001)
Four studies reported improved health outcomes
• Improved HRQOL in dimensions of general health (28% improvement, P < .001) and social functioning (26% improvement, P < .001) • Improved RQLP over 2 years
1. Salgado TM et al. Nephrol Dial Transplant. 2012;27:276-292. Review of Pharmacist-Managed Anemia CKD Clinics1
100 9.6 22.1 16.5 80 • Review of 16 VAMC clinics (2009) • 572 CKD patients over 6 months 60 71.1 51.7 56.9 • Pharmacist-based care 40 – More likely to achieve target Hb 20 31.8 – Reduced ESA use by up to 36% 19.3 21.0 0 Pharmacist ESA Usual care Usual care ESA clinic clinic
Hb >12 g/dL Hb 10-12 g/dL Hb <10 g/dL
1. Aspinall SL et al. Am J Kidney Dis. 2012;60:371-379. Review of Pharmacist-Managed Anemia CKD Clinics1 (Cont’d)
Retrospective longitudinal study comparing pharmacist-managed CKD to usual care (n = 101)
Improved outcomes
• 97% of patients achieve target hemoglobin • 20% reduction in average weekly ESA dose • $1,288/year annual savings per patient
1. Debenito JM et al. J Manag Care Spec Pharm. 2014;20:715-720. Review of Pharmacist-Managed Anemia CKD Clinics1 (Cont’d)
Case study: Pharmacist-Managed Anemia Clinic Improves Guideline Adherence for Darbepoetin
• 12-month pre/post implementation period • Two ambulatory care pharmacists (shared A/C and anemia clinics)
Outcomes • Reduced noncompliant ESA doses (32% vs 4%) • Improved physician satisfaction • Decreased physician workload • Improved Medicare reimbursement (Hb within 7 days and iron repletion prior to ESA)
1. Easley H, Cattron H, Dotter M. ASHP Practice Advancement Initiative (Case Study); 2017. Pharmacists Play a Valuable Role in the Management of CKD-Related Anemia
Collaborative Practice Agreements
Comprehensive CKD Management Anemia Management in CKD
Multiple disease state management Limited to anemia and iron management Key Components of CPA for Anemia Management in CKD
• State laws/regulations allow collaboration between physician and pharmacist
“A collaborative practice is defined as a practice in which the prescribing practitioner makes a diagnosis, maintains ongoing supervision of patient care, and refers the patient to a pharmacist, who may initiate and modify drug therapy
management within the protocol established by the
prescribing practitioner and the pharmacist”
• Credentialing requirements (ie, PharmD, residency, demonstrated competencies) Key Components of CPA for Anemia Management in CKD (Cont’d)
Examples of basic activities to be performed by pharmacist
1. Initiate and evaluate patients on ESA therapy and adjust dose based on response to therapy. 2. Initiate and evaluate patients with iron-deficiency anemia. 3. Order and evaluate the results of laboratory tests related to anemia therapy, including a. Hb/Hct e. TSAT b. Complete blood count (CBC) f. Ferritin c. Iron g. Vitamin B12 d. TIBC h. Folate 4. As an agent of the physician, prescriptions that are related to anemia management (ie, ESA, iron) can be written, faxed, or telephoned to the location of administration, typically the infusion center. 5. Each encounter will be documented in the electronic medical record.
• Dosing per treatment protocol or “Anemia Management Clinical Practice Guidelines” (KDIGO 2012) Kidney Disease Improving Global Outcomes (KDIGO)1
1. https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf. Accessed December 6, 2019. Kathryn: should title be different? Same as a few before
Key Components of CPA for Anemia Management in CKD
Collaborative agreement is signed by physician(s) and pharmacist(s)
Approval Signatures
______Janet Smith, PharmD
______Melissa Jones, MD Medical Director, CKD Program
______Margaret Emmons, PharmD Ambulatory Care Clinical Pharmacy Manager
______Jennifer Stephens, PharmD Pharmacy Director
Example CPAs: Key Elements
Major academic health center
Metro regional health center
Rural regional health center
Managed care system Kathryn: I changed slide title. Okay? Also, need ref?
Example CPAs
CPA Component Institution A Institution B Institution C Institution D
Nephrology ambulatory care clinical Pharmacist-managed Ambulatory care clinical pharmacy Name of service Pharmacist-managed CKD clinic pharmacist protocol – anemia in CKD anemia clinic specialist – renal clinic (renal CPS)
Reference to state law No Yes No No
Define collaborative practice? No Yes No Yes
HTN, DM, lipid, anemia, electrolytes, hematologic Disease states covered in Anemia in CKD (including iron Anemia in CKD (including complications, proteinuria, bone disease, Anemia and immunization in CKD CPA/Guideline replacement) iron replacement) hyperuricemia/gout, immunosuppression, infections, planning for RRT, nutrition, immunizations, renal drug dosing
Yes (all BL labs reviewed/corrected Yes (from MD) Referrals to anemia clinic Yes (from MD) Yes (from MD) prior to referral by MD) Can also refer to ED
PharmD does scheduling Not mentioned Yes Not mentioned Yes
Darbepoetin (SQ, every Epoetin apbx (SQ, every week), ESA prescribing rights Epoetin alfa (SQ, QW) Epoetin alfa/darbepoetin (SQ, every 1-4 weeks) 2-4 weeks) darbepoetin (SQ, every 4 weeks)
Nulecit (ferric gluconate): Iron prescribing rights Oral supplements, IV per protocol Yes Multiple one-time infusion
Hb every 2-4 weeks; CBC, iron, Hb/Hct, CBC, iron TIBC, Iron, ferritin, TSAT, CBC at baseline; Monitoring allowed Wide range TSAT quarterly, PTH as needed TSAT, ferritin, B12, folate Hb every 2 weeks Documentation/EMR Not mentioned EMR EMR EMR Kathryn: What RPh license, residency, competency, RPh license, practice privileges, demonstrated experience Credentials/requirements Not mentioned Not mentioned annual reviews, 2 hours CE in related area and competency in treating CKD patients should the “apbx” Ongoing review/QI Not mentioned Protocol reviewed annually CPA reviewed every 3 years Protocol reviewed every 2 years or as needed be spelled out PharmD, MD, Signatures on CPA Not mentioned PharmDs, MDs PharmD, MD, ACCP manager, chief pharmacist ambulatory care clinical manager to? Is it right? (under institution C column) Summary: The Role of Pharmacist in Emerging Therapies
• Benefits of pharmacist-managed CKD clinics are well documented
• Expanding collaborative practice agreements may include emerging therapies (HIF-PH inhibitors) when available and will likely have close monitoring for CV outcomes
• Advanced practice pharmacists will have an increasingly important role in value-based care settings!
Please remember to complete and submit your Post-Test and Evaluation for CPE credit. Missed anything?
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Thank you and have a good day.