The Beat Goes On: How to Assess Patients with Heart Failure. Robert Page, PharmD, MSPH and Lynne Sylvia, PharmD

The Beat Goes On: How to Assess Patients with Heart Failure Robert Page, PharmD, MSPH and Lynne Sylvia, PharmD

Target Audience: Pharmacists ACPE#: 0202-0000-18-047-L01-P Activity Type: Application-based Target Audience: ACPE#: Activity Type:

Disclosures Lynne Sylvia, PharmD: None Robert L Page, PharmD, MSPH: None Target Audience: ACPE#: Activity Type: The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Learning Objectives At the completion of this application-based activity, participants will be able to: 1. Discuss patient assessment tools that are appropriate for pharmacists to use when assessing patients with heart failure; 2. Evaluate pharmacologic options for management of heart failure; 3. Apply Target evidence-based Audience: findings and recommendations regarding ACPE#: the risks and benefits of pharmacologic treatments for heart failure to patient cases. 4. Develop Activity a care Type: plan that encompasses evidencebased medicine and pharmacoeconomic considerations.

1. Assessment Question What is the first step in initiating pharmacy-based care for a patient with heart failure? A. Perform Target Audience: medication reconciliation B. Assess current therapies for compliance with guidelinedirected ACPE#: therapies C. Establish a relationship with the patient D. Assess Activity medication Type: adherence with current therapies

2. Assessment Question Based on the signs/symptoms and physical findings, which of the following patients would be considered a cold and wet? A. 65 year old with Scr 2.0 mg/dl, + PND. B. 55 year old with warm extremities, +3 pitting edema. C. 80 year old with a narrow pulse pressure, -JVD. D. 75 year old with normal LFTs, extreme fatigue.

3. Assessment Question Which of the following has been associated with a falsely elevated serum BNP level? A. Obesity B. Pericarditis C. Pulmonary embolism D. Flash pulmonary edema

4. Assessment Question Which of the following statements is correct regarding treatment of hyperkalemia in a patient with HF on guideline-directed therapies? A. Treatment is only indicated when K exceeds 5.5 meq/l B. Modifiable Target Audience: factors include diet and drugs such as NSAIDs, trimethoprim, and some herbal preparations C. Aldosterone ACPE#: antagonist dosing should be reduced by 50% D. All guideline-directed therapies must be discontinued temporarily Activity Type: until hyperkalemia is resolved

Warm-Up Activity ---- Meet Vincent Vincent is a 51 year old Caucasian man recently diagnosed with HFrEF (LVEF 20 %) with NYHA Class 3 symptoms Referred to the Advanced HF Clinic; this is his first visit PMH: nonischemic CMP 2 months ago (possible etiology = familial), HTN, DM Type 2 Feels better than before his diagnosis but still fatigued with SOB Medications = carvedilol 3.125 mg po BID, furosemide 40 mg po BID, lisinopril 5 mg po once daily, spironolactone 25 mg po once daily, glimepiride 2 mg po once daily PE: BP 100/60, 95/55 on repeat; HR 97 and 104, RRR, JVP 14 cm at 90, no pedal edema, + abdominal bloating, weight = 170 lb (up from 162), A + O x 3 ROS: DOE, 2 pillow orthopnea, denies syncope or dizziness Labs: pending

Vincent: What Does His Story Tell You? Your observations: First visit Newly diagnosed HF On core guideline directed therapies but still symptomatic Weight is up by at least 5 pounds Low BP and tachycardic RRR Has diabetes

What Don t You Know about Vincent Labs - lytes, renal function, albumin, A1C What does he do for a living? (can influence medication adherence) Living situation? Family support? Prescription insurance and co-pays? Medication adherence? OTC use is he aware of avoidance of particular medications? Diet sodium and volume intake? Has he ever been educated about HF and its management? Does he know his dry weight? Does he own a scale?

Where do You Begin to Provide Care? What is the first step in initiating pharmacy-based care for Vincent? A. Perform medication reconciliation B. Assess current therapies for compliance with guidelinedirected therapies C. Establish a relationship with the patient D. Assess medication adherence with current therapies

HF Consultation: Where do you Begin? Medication Reconciliation Collect Compare Correct Communicate Allergy/Intolerances Education for Self-Care Symptom tracker Medications Diet and Fluid Intake Provider Access The Four Pillars Plus 1: Establish a Relationship Guideline- Directed Therapies Know the recent guidelines and hallmark RCTs Assess appropriateness of therapy Document, document, document Transition of Care Follow-up Phone Call Home visit Telemonitoring

Additional Essential Roles: HF Pharmacists Ensuring Drug Access Prior authorizations, patient assistance programs Education on Complex Therapies Self-administration of enoxaparin as outpatient, insulin regimens, conversion from ACEIs or ARBs to sacubitril/valsartan, IV iron Pill Box fills or blister packs Anticoagulation Monitoring for patients with mechanical assist devices (LVADs) IV infusion therapies: home milrinone or dobutamine infusion, IV diuretic clinics Heart transplant patients: evaluations, drug level monitoring, education Protocol development for Complex Therapies

To be effective HF Guidelines and Hallmark RCTs Patient Assessment Tools Customized Educational Materials Empathy and Compassion Listening skills Time-Efficient Strategies Team-based Attitude You may need to shore up your Toolbox!

Our Ultimate Goal for this Session Using a series of patient scenarios Illustrate how you provide optimal integrated care to the patient with chronic heart failure through Outreach and relationship building, Knowledge of guideline-directed therapies, Effective use of available tools including physical assessment, Effective communication.

Case 1 C.J. is a 75-year-old man (height 5 8, weight 72 kg) with ischemic cardiomyopathy (EF 30%) presenting to the emergency room with worsening dyspnea on exertion, orthopnea, and paroxysmal nocturnal dyspnea. PMH: CAD, hyperlipidemia, hypertension, and CKD. Vital signs: BP 117/68 mm Hg, HR 75 beats/minute, RR 23 breaths/minute, and oxygen saturation 94% on 4 L nasal cannula.

Case 1 Physical Exam: JVD to his ear lobe, rales bilaterally, and 3+ bilateral lower extremity edema to his knees, but only mild abdominal edema. He admits a 10-lb weight gain in the past 2 weeks after running out of his home drugs. Pertinent laboratory values: sodium 136 mmol/l, potassium 4.8 mmol/l, BUN 59 mg/dl, SCr 1.9 mg/dl (baseline 1.7 mg/dl), N- terminal probnp 4530 pg/ml (baseline 1800 pg/ml), AST 20 U/L, ALT 10 U/L.

Review of Function Class and Stages A B C ACCF/AHA Stages of HF At high risk for HF but without structural heart disease or symptoms of HF Structural heart disease but without signs or symptoms of HF Structural heart disease with prior or current symptoms of HF None I I NYHA Functional Classification No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF. No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF. II III Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF. Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF. Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest. IV D Refractory HF requiring specialized interventions Circulation. 2013; 128:e240-e327. IV Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest.

Testing and Medication Titration Following Diagnosis of HFrEF Used with Permission. Yancy et al. JACC. 2017. Published ahead of print. Available at: http://www.onlinejacc.org/content/early/2017/12/12/j.jacc.2017.11.025. Accessed January 13 2018

Essential Components of the Heart Failure Examination General Appearance Vital Signs in recumbent and upright positions Heart Rate Blood Pressure Jugular Venous Pressure/Hepatojugular Reflux Auscultation of the chest, percussion as needed Examination for peripheral edema and perfusion: As needed or observed: Skin appearance and temperature (to touch) of hands and feet Pulse character, contour, and duration (carotid and/or femoral sites) Number of pillows (measure of orthopnea)

Hemodynamic Correlates of Major Physical Findings Jugular Vein Jugular venous pressure (in the absence of atrioventricular valvular stenosis): approximates right ventricular diastolic pressure and can provide a clue to the state of left ventricular diastolic pressure Hepatojugular (abdominojugular) reflux of 3 cm when jugular venous pressure is <10 cm: marginal or mild volume overload Blood Pressure Epomedicine. Jugular Venous Pressure. Available at:http://epomedicine.com/clinical-medicine/clinical-examination-jugularvenous-pulse-pressure-jvp/. Accessed December 10, 2017. Rated Medicine. Jugular Venous Pressure. Available at: https://ratedmedicine.wordpress.com/jugular-venous-pressure/. Accessed December 10, 2017.

Hemodynamic Correlates of Major Physical Findings https://www.youtube.com/watch?v=qvavuwgmf54

Hemodynamic Correlates of Major Physical Findings Precordium Left parasternal lift (right ventricular heave): right ventricular pressure and/or volume overload Hypokinetic (weakened) ventricular impulse: decreased ventricular contractility, often a reduced ejection fraction Wide, sustained left ventricular impulse (>50% of systole): increased left ventricular mass Laterally displaced left ventricular impulse: ventricular chamber enlargement Reduced intensity of S1 with unchanged PR interval: elevation of left ventricular end diastolic pressure Increased intensity of P2: pulmonary arterial hypertension S4 gallop: increased ventricular stiffness in diastole (reduced ventricular compliance) S3 gallop in adults (without severe atrioventricular valve regurgitation or pregnancy): increased ventricular diastolic pressure and filling Systolic murmur along lower left sternal border, which increases on inspiration: tricuspid regurgitation

Hemodynamic Correlates of Major Physical Findings Extremities Dependent edema: often volume overload Cool, moist hands and feet: low cardiac output, increased sympathetic tone, and elevated SVR Assessing Pitting Edema Trace Minimal depression noted when pressure applied +1 Application of pressure creates a depression of 2 mm; no visible distortion; rapid return of skin to position +2 Application of pressure creates a depression of 4 mm in depth that disappears in about 10-15 seconds +3 Application of pressure creates a depression of approximately 6mm in depth that lasts 1-2 minutes; area may appear swollen +4 Application of pressure creates a depression up to 8 mm in depth that persists for 2-3 minutes; area is grossly edematous

Hemodynamic Correlates of Major Physical Findings Extremities Congestion No Yes Low Perfusion CI 2.2 No Warm & Dry Yes Cold & Dry Warm & Wet Cold & Wet Signs/Symptoms of Congestion: Orthopnea/PND JV Distention Hepatomegaly Edema Rales Abd-Jugular Reflux PCWP 18 Signs/Symptoms of Low Perfusion: Narrow pulse pressure Cool Extremities Sleepy/obtunded Hypotension Low serum sodium Renal/Hepatic dysfunction

Roles of BNP and NT-proBNP: Correlate with LVED wall stress Support diagnosis Predict mortality, HF events Guide therapy and make adjustments Does NOT improve outcomes (GUIDE-IT Trial) Circulation. 2017. 135(22):e1054-e1091

Other Important Laboratory Findings: Natriuretic Peptides Cutoff Value pg/ml Sensitivity % Specificity % PPV % NPV % To Exclude Acute Heart Failure BNP <30-50 97 62 71 96 NTproBNP <300 99 68 62 99 To Identify Acute Heart Failure (Single Cut Off Strategy) BNP <100 90 76 79 89 NTproBNP <900 90 85 76 94 Cardiac Biomarkers. Expert Analysis. American College of Cardiology. 2015. Available at: http://www.acc.org/latest-in- Cardiology/%20articles/%202015/%2002/09/13/00/cardiac-biomarkers-and-heart-failure. Accessed January 13, 2018.

Other Important Laboratory Findings: Natriuretic Peptides BNP, gray Zone NT-ProBNP Cutoff Value pg/ml Sensitivity % Specificity % Multiple Cut Point Strategy for Acute Heart Failure PPV % NPV % <100, to exclude 90 73 75 90 100-400 gray zone???? >400,to rule in 63 91 86 74 <300, to exclude 99 62 55 99 <450 for age <50 years, to rule in 97 93 76 99 <900 for age 50-75 years, to rule in 90 82 82 88 <1800 for age >75 years, to rule in 85 73 92 55 Cardiac Biomarkers. Expert Analysis. American College of Cardiology. 2015. Available at: http://www.acc.org/latest-in- Cardiology/%20articles/%202015/%2002/09/13/00/cardiac-biomarkers-and-heart-failure. Accessed January 13, 2018.

Other Important Laboratory Findings: Natriuretic Peptides Higher Natriuretic Peptide Levels Than Expected Increasing age* ACS* Renal insufficiency RV dysfunction AF Pulmonary hypertension* Pulmonary embolism* Anemia/high out states* Sepsis Mitral regurgitation* Lower Natriuretic Peptides Than Expected Obesity Flash pulmonary edema Pericarditis/tamponade Genetic polymorphisms End-stage cardiomyopathy ACS=Acute coronary syndrome, AF=Atrial fibrillation, RV = Right ventricular. *Delineates likely elevation from ventricular stretch Circulation. 2017. 135(22):e1054-e1091

3. Assessment Question Which of the following has been associated with a falsely elevated serum BNP level? A. Obesity B. Pericarditis C. Pulmonary embolism D. Flash pulmonary edema

Case 1: Think Pair Share 1. On physical exam, what physical findings suggest HF exacerbation? 2. How would you classify this patients HF? 3. How would you interpret this patients BNP?

Case 1: Think Pair Share Meds: atorvastatin 40 mg/day, aspirin 81 mg/day, enalapril 10 mg twice daily, carvedilol 12.5 mg twice daily, digoxin 125 mcg/day, and furosemide 40 mg twice daily. 1. After evaluating this patients sign/symptoms, what should be done with this patient s diuretic regimen? What dose would your recommend? 2. What should be done with this patients ACE-inhibitor? 3. What about the beta-blocker?

Drug Titration of GDMT for HFrEF Used with Permission. Yancy et al. JACC. 2017. Published ahead of print. Available at: http://www.onlinejacc.org/content/early/2017/12/12/j.jacc.2017.11.025. Accessed January 13 2018

DOSE-AHF: Diuretic Titration in Acute Heart Failure Acute Heart Failure (1 symptom AND 1 sign) <24 hours after admission 2x2 factorial randomization Low Dose (1 x oral) Q12 IV bolus Low Dose (1 x oral) Continuous infusion High Dose (2.5 x oral) Q12 IV bolus High Dose (2.5 x oral) Continuous infusion 48 hours 1) Change to oral diuretics 2) continue current strategy 3) 50% increase in dose 72 hours Co-primary endpoints 60 days New Engl J Med. 2011; 364: 797-805. Clinical endpoints

Primary Endpoint: Change in Visual Analogue Scale 100 VAS assessed at 6, 12, 24, 48, 72 hours 90 80 Visual Analog Scale 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 70 Hours New Engl J Med. 2011; 364: 797-805.

Secondary Endpoints:Q12 vs. Continuous Q12 Continuous P value Dyspnea VAS AUC at 72 hrs 4456 4699 0.36 % free from congestion at 72 hrs 14% 15% 0.78 Change in weight at 72 hrs -6.8 lbs -8.1 lbs 0.20 Net volume loss at 72 hrs 4237 ml 4249 ml 0.89 Change in NTproBNP at 72 hrs (pg/ml) -1326-1773 0.44 % treatment failure 38% 39% 0.88 % with Cr increase > 0.3 mg/dl 17% 19% 0.64 within 72 hrs Length of stay, days (median) 5 5 0.97 New Engl J Med. 2011; 364: 797-805.

Secondary Endpoints: Low vs. High Intensification Low High P value Dyspnea VAS AUC at 72 hours 4478 4668 0.041 % free from congestion at 72 hrs 11% 18% 0.091 Change in weight at 72 hrs -6.1 lbs -8.7 lbs 0.011 Net volume loss at 72 hrs 3575 ml 4899 ml 0.001 Change in NTproBNP at 72 hrs (pg/ml) -1194-1882 0.06 % Treatment failure 37% 40% 0.56 % with Cr increase > 0.3 mg/dl 14% 23% 0.041 within 72 hrs Length of stay, days (median) 6 5 0.55 New Engl J Med. 2011; 364: 797-805.

Proportion with Worsening Renal Function*: Low vs. High 25% P > 0.05 for all timepoints % with Δ Cr > 0.3 mg/dl 20% 15% 10% 5% Low High 0% 0 1 2 3 4 7 60 Days New Engl J Med. 2011; 364: 797-805. *Based on local lab creatinine values

Death, Rehospitalization, or ED Visit HR for Continuous vs. Q12 = 1.19 95% CI 0.86, 1.66, p = 0.30 HR for High vs. Low = 0.83 95% CI 0.60, 1.16, p = 0.28 Proportion with Death, Rehosp, or ED Visit 0.6 0.5 0.4 0.3 0.2 0.1 Continuous Q12 Proportion with Death, Rehosp, or ED visit 0.6 0.5 0.4 0.3 0.2 0.1 High Low 0 0 10 20 30 40 50 60 Days 0 0 10 20 30 40 50 60 Days New Engl J Med. 2011; 364: 797-805.

Case 2 PH is a 75 y/o, 70-kg man with a 2 year history of HFrEF (EF 25%), NYHA class III, and a history of one hospitalization in the past 6 months presents for a regular f/u visit. Chief complaint of extreme fatigue and external dyspnea Current meds: carvedilol, furosemide, potassium chloride, losartan, aspirin, spironolactone, citalopram, acetaminophen, zolpidem, and vit D

Case 2 PMH: STEMI ( 2 years ago), HTN, DM (diet controlled), HFrEF (LVEF: 40%, NYHA class III), Hyperlipidemia, and depression Routine labs : SCr 1.4 mg/dl, calculated CrCl = 45 ml/min K+ 4.5 mmol/l HgA1c 7.2 mg/dl Hb 10.5 g/dl Low MCV Ferritin 150 ng/ml Tsat 14%

Iron-Deficiency : Epidemiology in HF Iron deficiency occurs in > 1/3 of patients with HF Common cause of anemia More likely to occur in women vs men Prevalence increases with HF disease severity 2 types of iron deficiency Absolute: depleted iron stores, with intact iron homoeostasis mechanisms Common causes: low-dietary intake, impaired GI absorption, GI blood loss, menorrhagia Functional: normal or high iron body stores, but iron is trapped inside cells of the reticuloendothelial system and is unavailable for cellular metabolism JACC. 2008;52:818-27; Circulation. 2006;113:2454-61. Heart Failure Clin. 2010;6:279-88; JACC. 2006;48:2485-9; Eur Heart J. 2010;31:1872-80; Eur Heart J. 2013; 34(11): 816 829.

Iron-Deficiency : Pathophysiology in HF Renal dysfunction, neurohormonal and proinflammatory cytokine activation Inappropriate erythropoietin production and defective iron utilization, leading to intestinal iron absorption and accumulation within the reticuloendothelial stores Hemodynamic responses to hypoxia: vasodilationmediated high-output state with neurohormonal activation to increase oxygen transport Heart Fail Clin. 2010;6(3):279-88; Eur Heart J. 2013; 34(11): 816 829.

Eur Heart J. 2013;34(11):816-29. Mortality with Iron-Deficiency in HF

Iron-Deficiency Anemia: Symptoms Fatigue Exercise intolerance Exertional dyspnea Chest pain Weakness Headache Irritability Vertigo

Iron-Deficiency Anemia: Diagnosis CBC Low Hemoglobin (Hb) <13 g/dl (men) or <12 g/dl (women) May have low mean corpuscular volume (MCV) or mean corpuscular hemoglobin (MCH) Serum ferritin May be low (<100 ng/ml = absolute iron deficiency) May be normal (100-300 ng/ml = functional iron deficiency) Iron binding panel = transferrin, % transferrin saturation (Tsat), total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC) Tsat <20% accompanied by normal ferritin = functional iron deficiency May also want to consider ordering serum vitamin B12. JACC. 2006;48:2485-9.; Eur Heart J. 2013; 14; 34(11): 816 82.

Iron Absorption Iron is absorbed in the upper GI tract Duodenum is the site of maximal absorption Mucosal cells are responsible for iron absorption, and older adults with certain conditions may absorption Celiac disease, atrophic gastritis, H. pylori infection, and previous bariatric surgery

Clinical Investigation of Iron Replacement TRIAL INCLUSION CRITERIA FERRIC-HF 2008 Ferritin <100 ng/ml or 100-300ng/mL w/tsat <20%; Hb 14.5 g/dl; NYHA II-III; EF 45% J NEPHROL 2008 Hb <11 g/dl, NYHA III-IV FAIR-HF 2009 Ferritin <100 ng/ml or 101-299ng/mL w/ TSat <20%; Hb 9.5-13.5g/dL NYHA II-III, HFrEF 40-45% IRON-HF 2013 Ferritin <500 ng/ml and TSat <20%; Hb 9-12 g/dl; Hb 9-15 g/dl; NYHA II-III, III), LVEF<40% CONFIRM-HF 2015 Ferritin <100 ng/ml or 100-300ng/mL w/ TSat <20%; Hb <15 g/dl; Symptomatic HFrEF 45%, NYHA II-III, and high BNP IRONOUT-HF 2017 Ferritin <100 ng/ml or 101-299ng/mL w/ TSat <20%; NYHA II-III, HFrEF 40% EFFECT-HF Abstract Ferritin <100 ng/ml or 100-300ng/mL w/tsat <20%; Hb <15 g/dl; NYHA II-III, HFrEF 45% J Am Coll Cardiol 2006;48:1225-1227; J Am Coll Cardiol 2008;51:103-112; J Nephrol 2008;21:236-242; N Engl J Med 2009; 361:2436-2448; Int J Cardiol 2013;168:3439-3442; Eur Heart J. 2015; 36:657-68.; 7. JAMA 2017;317(19):1958-1966

Clinical Investigation of Iron Replacement TRIAL N DRUG REGIMEN FERRIC-HF 2008 35 IV IS 200 mg/wk until ferritin >500, then Qmo; or no treatment J NEPHROL 2008 32 IV IS 100mg TIW x 3wks, then weekly x 23wks FAIR-HF 4 2009 459 IV FCM 200mg weekly, then Qmo starting at wk 8 or 12; or placebo Used Ganzoni formula 9 IRON-HF 5 2013 23 IV IS 200 mg/wk x 5 wks or FeSO 4 200mg TID X 8wks or placebo CONFIRM-HF 6 2015 304 IV FCM 500-1000 mg based on weight/hb at weeks 0, 6; 500mg at wks 12, 24, and 36 depending upon Tsat and ferritin or placebo IRONOUT-HF 7 2017 225 Oral iron polysaccharide 150mg BID or placebo EFFECT-HF 8 Abstract 174 IV FCM at weeks 0, 6 and 12; or placebo ± oral iron IV IS = IV Iron sucrose = Venofer ; IV FCM = Ferric carboxymaltose = Injectafer J Am Coll Cardiol 2006;48:1225-1227; J Am Coll Cardiol 2008;51:103-112; 3; J Nephrol 2008;21:236-242; N Engl J Med 2009; 361:2436-2448; 5. Int J Cardiol 2013;168:3439-3442; Eur Heart J.2015; 36:657-68; JAMA 2017;317(19):1958-1966.

Clinical Investigation of Iron Replacement TRIAL FERRIC-HF 2008 16-wk f/u Mean dose: 1433mg J NEPHROL 2008 26 wk f/u Mean dose: 3200mg FAIR-HF 2009 24 wk f/u Median dose 2000 mg OUTCOMES Hb (by 0.1), ferritin (by 273), Tsat (by 11) Improved exercise capacity, improved symptoms; effects if anemic Hb (by 3), ferritin (by 40), Tsat (by 13-18) Improved functional class from III to II and improved cardiac defects and LVEF in class III patients; less robust response in class IV patients Significant improvement in patient global assessment (50% much/moderately improved vs 28%, OR 2.51) Significant improvement in functional class (47% class I or II vs 30% at wk- 24, OR 2.40) and significant improvement in 6MW test and QOL Results similar in patients with anemia/no anemia No difference in death or adverse events J Am Coll Cardiol. 2006;48:1225-1227; J Am Coll Cardiol. 2008;51:103-112; 3. J Nephrol. 2008;21:236-242; N Engl J Med. 2009; 361:2436-2448

Clinical Investigation of Iron Replacement TRIAL IRON-HF 2013 12 wk f/u Mean dose: 1000 mg CONFIRM-HF 2015 52 wk f/u Mean dose: 1500 mg IRONOUT-HF 2017 16 wk f/u Oral 150mg BID OUTCOMES No diff in Hb between oral/iv iron, ferritin in oral & IV iron (only significant w/oral iron), Tsat significantly in IV compared to placebo VO 2 max increased in IV iron group but not oral iron group Significant improvement in 6MW, NYHA class, PGA, QOL & fatigue starting at week 24 consistent amongst all subgroups through wk52 Significant reduction in hospitalization for worsening HF (HR 0.39) and trend for reduction in hosp due to any CV reason (HR 0.63) No difference in deaths or adverse event Significant Tsat (2 pts); Nonsig ferritin (18 pts) No difference in change in VO 2 max No difference in 6MW distance, NT-proBNP levels or KCCQ QOL score Int J Cardiol 2013;168:3439-3442; Eur Heart J.2015; 36:657-68.; JAMA 2017;317(19):1958-1966

2017 AHA/ACC Guideline Recommendations Routine evaluation of HF patients should include evaluation for anemia In patients with HF and anemia, erythropoietin-stimulating agents should not be used to improve morbidity/mortality

Case 2-Questions for Discussion 75 y/o, 70-kg man with a 2 year history of HFrEF (EF 25%), NYHA class III, and a history of one hospitalization in the past 6 months presents for a regular f/u visit Current meds: carvedilol, furosemide, potassium chloride, losartan, aspirin, spironolactone, citalopram, acetaminophen, zolpidem, and vit D Routine labs are checked SCr 1.4 mg/dl, calculated CrCl = 45 ml/min K+ 4.5 mmol/l Hb 10.5 g/dl Low MCV Ferritin 150 ng/ml Tsat 14% Should this patient be treated with oral iron? Should this patient be treated with IV iron?

IV Ferric Carboxymaltose FDA approved for iron-deficiency anemia in adults with CKD or those who have intolerance to oral iron or have had an unsatisfactory response to oral iron Dose: FDA approved 750mg weekly X 2 doses if >50 kg? re-dosing like in clinical studies to maintain ferritin/tsat IV infusion over at least 15 min or slow IV push over at least 7.5 min Some clinical trials gave over 1 min Monitor for hypersensitivity and increases in BP for 30 min after administration Adverse effects: nausea (7%, all others <5%), HTN, HA, dizziness, vomiting Cost: $1200 per 750 mg/15 ml single-use vial Insurance coverage: likely covered by Medicare Part B and commercial plans, possibly with PA, Medicaid may/may not cover

Return to the Beginning Vincent First visit: BP 95-110/55-60, NSR with HR 100, JVD, abdominal edema, DOE, 2 pillow orthopnea Carvedilol 3.125 mg po BID, lisinopril 5 mg daily, furosemide 40 mg po BID, spironolactone 12.5 mg po once daily Labs: AIC 6%, Na 137, K 4.6, BUN/Scr 16/1.43, BNP 937, H/H 14.4/42 Changed furosemide to torsemide and reduced lisinopril to 2.5 mg po daily First Visit with Pharmacist: Establish a relationship Medication Reconciliation Insurance Assessment/Drug Access/Adherence Education: Action Zones Weight management/scale Time of diuretic dosing Call back in 48 hours to reinforce plan

Action Zones If weight is increased by 3 lbs in a day or 5 lbs, in a week, take an extra dose of torsemide www.riseabovehf.org

One year later Vincent CC - I have more energy. According to my FitBit, I am walking at least 5,000 steps a day. I only get short of breath when I climb stairs - I can t do stairs well Current Medications: carvedilol 6.25 mg po BID, sacubitril-valsartan 49/51 mg po BID, spironolactone 12.5 mg po once daily, torsemide 20 mg po BID (reduced dose) Vital signs: BP 110/65 mm Hg, HR 65, weight 160 lbs (dry weight) PE: - JVD, RRR, - peripheral edema, - abdominal edema ROS: reports improved appetite and activity level, DOE only with stairs, - PND, in Green Zone most days, takes an extra dose of torsemide once every 2 weeks Labs: K 5.6, BUN/Scr 32/1.4 History: K 5.0 to 5.4 after 1 month on sacubitril/valsartan plus spironolactone Reduced spironolactone to 12.5 mg (from 25 mg) 1 month ago Educated on low potassium diet

Hyperkalemia in HF The Evidence Serum K should be maintained below 5 meq/l Potassium > 5.5 meq/l should generally trigger dose reduction or drug discontinuation Yancy CW et al. Circulation 2013; 62(16): e147-239 Clinical Trials of ACEIs, ARBs and AAs in HF: Mild hyperkalemia = > 5 but < 5.5 meq/l Moderate hyperkalemia = 5.5but<6mEq/L Severe hyperkalemia = 6 meq/l Levels 5.5 meq/l or greater are of concern and should prompt discontinuation of one or more offending drugs with short-term follow-up to confirm a return to normal Desai AS. Current Heart Failure Reports 2009;6:272-280 Our patient: K 5.6 meq/l; Sustained Not controlled by diet alone Reduced diuretic requirement

Treatment of Chronic, Persistent Hyperkalemia Modifiable Factors: Dietary considerations: Decrease high potassium foods (e.g., avocados, raisins, squash) Remove non-hf medications that are contributory NSAIDs, trimethoprim, herbal agents Reduce doses of guideline-directed therapies (ACEIs, ARBs and AAs) Oral potassium binding resins and polymers Premise of GI Resins and Polymers: Normally, 90% of K removed via kidneys and 5-10% via colon into stool In CKD, colonic secretion of K via BK channels increases as an adaptive phenomenon Colonic secretion may be up-regulated 2 to 8 fold Cationic exchange resins bind to potassium in the colon and facilitate K excretion in stool

Cation Exchange Resins Sodium polystyrene sulfonate (SPS; Kayexalate ) Patiromer (Veltassa ) Approval 1958 October 2015 Action Exchanges sodium for K Each 1 gram of SPS provides 100 mg Na (30 grams = 3000 mg Na) Co-formulated with sorbitol (20 grams) Dose 15 to 60 grams 1-4 times a day 30-50 grams PR every 6 hours Warnings Intestinal necrosis Low magnesium and calcium Binding to medications Adverse Effects Cost per day Edema, Hypokalemia, Constipation, Diarrhea Exchanges calcium for K Acts predominantly in the distal colon where K [ ] is the highest Minimal calcium absorption Sorbitol content: 4 grams (8.4 g dose) 8.4, 16.8 or 25.2 g packets orally/day with food Worsening of GI motility Hypomagnesemia Binding to medications Constipation (11%), Magnesium wasting (5.3%), Hypokalemia (4.7%) $/dose x 2 to 3 doses/day $$$/dose x 1 dose per day

The Evidence in HF Sodium polystyrene sulfonate (SPS; Kayexalate ) Study Data Uncontrolled studies, retrospective cohorts (including 14 patients on RAASi) Total < 150 Duration of Study Up to 14.5 months (14 patients) 1-280 days (32 patients) Onset > 2 hours; maximal effect in > 6 hours Extent of potassium reduction - 0.14 meq/l after 1 dose (15 g) No change at 4, 8 and 12 hours (30 g dose) At 14.5 months, -1.8 meq/l (n=14 HF patients on RAASi) After 7 days, mean -1.04 meq/l (95%CI -0.71 to -1.37 meq/l) Patiromer (Veltassa ) RCTs of patients with CKD, DM and HF with hx hyperk on RAASi Total 654 (48% with HF on RAASi) 12 weeks (HF) 52 weeks (CKD, DM) ~7hours By 7 hours, -0.21 meq/l (mean) At week 4, -1.06 meq/l ± 0.05 Meaney CJ et al. Pharmacotherapy 2017;37(4): 401-11

Patiromer in Heart Failure The Evidence Study Inclusion Criteria Study Sample Intervention Results PEARL-HF N= 105 Pitt B et al. Eur Heart J 2011; 32(7): 820-828. OPAL-HK N=243 Pitt B et al. European J Heart Failure 2015;17:1057-65. Baseline K 4.3 to 5.1 And HF with indication to start spironolactone in addition to EITHER 1) history of hyperk within past 6 months that led to ACEI/ARB or AA d/c or 2) CKD (crcl < 60 ml/min) with continued ACEI/ARB Baseline K 5.1 to 6.5 And CKD Stages 3 or 4 (15 to 60 ml/min), on a stable dose of 1 RAASi for 28 days. Excluded HF Stage 4, DM1, OHT or kidney transplant NYHA Classes II or III (87%); 41% had hx hyperk due to ACEI/ARB/AA; 50%CKD; DM 30% 70% receiving an ACEI or ARB plus a beta-blocker 42% HF (65% NYHA Class II), 44% CKD3, DM 54% N=102 with HF Dual RAASi 25 (25%) ACEI 70 (69%) ARB 36 (36%) AA 20 (20%) 38% mild hyperk; 62% moderate to severe Patiromer 15 grams BID (n=55) versus placebo (n=49); 4 week study Introduction of spironolactone 25 mg/day; titrated to 50 mg/day in 2 weeks if K 5.1 Phase 1 (4 weeks): 4.2 or 8.4 grams patiromer BID based on initial K level Phase 2 (8 weeks): 49 HF patients randomized to patiromer ONCE daily (n=27) or placebo (n=22) if K had reduced to 3.8 to < 5.1 during phase 1. Treatment algorithm for hyperk/hypok MeandifferenceinK-0.45 meq/l favoring patiromer (p<001); K >5.5 in 7% v 25% (p=0.015); Spironolactone 50 mg/day in 91% v. 74% (p=0.019); Hypokalemia (<3.5) in 6% v. 0% At 4 weeks, mean change in K was -1.06±0.05 meq/l (p<0.001); 76% met the target range At 12 weeks, recurrence of hyperk (> 5.5) in 8% patiromer group v. 52% of placebo (p<0.001). RAASi continued in 100% patiromer group v 55% placebo

Patiromer Dose: Starting Dose = 8.4 grams once daily with food Adjust dose by 8.4 grams daily at one week intervals Maximum dose = 25.2 grams daily Administration: Add 1 ounce water to empty cup Empty drug contents into cup Stir thoroughly Add additional 2 ounces water to admixture in cup Stir thoroughly; will appear cloudy Drink immediately; Add water if needed to residue in cup Limitations: 1) Binding Issues: Of the oral medications studied with patiromer (n=28), 50% bound to the drug. Medications NOT found to bind: lisinopril, valsartan, spironolactone Drugs of concern: amlodipine, furosemide, levothyroxine, metoprolol ALL other medications need to be taken at least 3 hours before or after patiromer 2) Lack of data in OHT patients: Binding to Mycophenolate? Effectiveness in patients on CNIs? 3) Maximum study duration: 12 weeks in HF patients

https://www.fda.gov/downloads/drugs/drugsafety/ucm574818.pdf UPDATE: Sodium Polystyrene and Medication Binding

The Big Question Treatment What is your recommendation for management of hyperkalemia in this case? A) Reduce dose of sacubitril/valsartan B) Discontinue spironolactone C) Prescribe sodium polystyrene sulfonate 15 grams x 1 with repeat lab D) Prescribe patiromer 8.4 grams daily x 2 doses then repeat labs E) No treatment at this time; repeat lab in 24 hours The Case: Vincent Chronic hyperkalemia not responsive to diet alone Responding well to guidelinedirected therapies Sacubitril-valsartan 49/51 mg BID, spironolactone 12.5 mg po daily, carvedilol 6.25 mg po BID Asymptomatic hyperkalemia; NSR K 5.6; crcl ~ 61 ml/min; AIC 5.5%

The Decision (and the Role of the Pharmacist) Patiromer 8.4 grams once daily Repeat labs in 48 hours No change in dosing of guideline directed therapies Pharmacist s Role: Process prior authorization Assess affordability of agent Ensure access to medication (availability) Counsel patient on expected side effects Counsel patient on need to space dosing Administer patiromer in midday with meal Re-educate on avoidance of K rich foods Call back in 48 hours to ensure that patient went to the lab

A helpful checklist to consider for discharging patients from clinic and for follow-up phone calls Follow-Up: K was 4.6 meq/l in 3 days; patient continued on patiromer as daily therapy One month later: patiromer dosing three times a week https://www.heart.org

Ten Considerations to Improve Adherence 1. Capitalize on opportunities when patients are most disposed to adherence In-hospital/pre-discharge initiation following decompensation 2. Consider the patient s perspective Start with the goals of therapy (feeling better and living longer) and then discuss how specific actions (medication initiation, intensification, monitoring, and adherence) support those goals Use decision aids when available Ask patient how they learn best and provide education accordingly 3. Simplify medication regimens whenever possible

Ten Considerations to Improve Adherence 4. Consider costs and access Become familiar with and advocate for systems that help make cost sharing automatic, immediate, and transparent Prescribe lower-cost medications if of similar efficacy Facilitate access to copay assistance Discuss out-of-pocket copays proactively Prescribe 90-day quantities for refills 5. Communicate with other clinicians involved in care, ideally facilitated by electronic health records Yancy et al. JACC. 2017. Published ahead of print. Available at: http://www.onlinejacc.org/content/early/2017/12/12/j.jacc.2017.11.025. Accessed January 13, 2018.

Ten Considerations to Improve Adherence 6. Educate using practical, patient-friendly information Provide a written explanation of the purpose of each medication prescribed Plan pharmacist visits for complex medication regimens Use the teach back principle to reinforce education 7. Recommend tools that support adherence in real time Pill boxes to be filled by patient or caregiver a week at a time Alarms for each time of the day medications are due Smartphone M-Health applications that provide an interactive platform for education, reminders, warnings, and adherence tracking 8. Consider behavioral supports Motivational interviewing Participate in engaged benefit designs Yancy et al. JACC. 2017. Published ahead of print. Available at: http://www.onlinejacc.org/content/early/2017/12/12/j.jacc.2017.11.025. Accessed January 13, 2018.

Ten Considerations to Improve Adherence 9. Anticipate problems Communicate common side effects Provide instructions on when to call for refills or problems 10. Monitor adherence and target patients at risk Ask patients directly (e.g., How many times in a week do you miss taking your medications? Have you run out of your medications recently? ) Carry out medicine reconciliation at visits, with focus on discrepancies Assess remaining dosage units (i.e., count excess remaining tablets) Review available drug levels (e.g., digoxin, INR) or concentrations of BNP/NT-proBNP Plan home-based nursing visits for appropriate patients Yancy et al. JACC. 2017. Published ahead of print. Available at: http://www.onlinejacc.org/content/early/2017/12/12/j.jacc.2017.11.025. Accessed January 13, 2018.

The Wrap Up Physical assessment can be a powerful tool when evaluating patients with heart failure and titrating drug therapy. Both iron deficient anemia and hyperkalemia are common comorbidities in patients with heart failure which warrant close coordination of care. With a solid understanding of the consultation process as well as having the appropriate educational and assessment tools, pharmacists can make significant impacts on outcomes in patients with heart failure.

Patient Tools www.heartfailurematters.org