The Pharmacist s Role In Optimizing Outcomes for Heart Failure. The Pharmacist s Role In Optimizing Outcomes for Heart Failure. Educational Objectives

Transcription

1 The Pharmacist s Role In Optimizing Outcomes for Heart Failure The Pharmacist s Role In Optimizing Outcomes for Heart Failure Toby C. Trujillo, PharmD, FCCP, FAHA, BCPS-AQ Cardiology Associate Professor of Clinical Pharmacy University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences Clinical Specialist Cardiology/Anticoagulation Director Inpatient Anticoagulation/Thrombosis Management Service University of Colorado Hospital Aurora, Colorado Robert J. DiDomenico, PharmD, BCPS-AQ Cardiology, FCCP Clinical Professor of Pharmacy Practice University of Illinois at Chicago College of Pharmacy Cardiovascular Clinical Pharmacist University of Illinois Hospital & Health Sciences System Chicago, Illinois Educational Objectives This activity is supported by an educational grant from Novartis Pharmaceuticals Corporation. At the completion of this activity, the participant will be able to: Explain the place in therapy for sacubitril/valsartan and ivabradine Analyze clinical guidelines to develop an optimal medication regimen for a patient with heart failure Characterize the pharmacist s role in preventing readmissions for heart failure Heart Failure: The Cold Hard Facts HEART FAILURE STATISTICS, PATHOPHYSIOLOGY, & GUIDELINE-DIRECTED MEDICAL THERAPY 5.7 million adults in the United States have heart failure (HF) (2012) Prevalence will increase 46% by ,000 new cases annually By age 40, lifetime risk = 1:5 adults Hypertension (HTN) MAJOR risk 75% of HF cases have HTN Lifetime risk 2x higher Mortality ~30% at 1 year ~50% at 5 years Hospitalizations ~1 million annually Mortality 28 days: 10.4% 1 year: 29.5% Annual Cost $30.7 billion (2012) Direct costs: $20.9 billion Mozaffarian D, et al. Circulation. 2016;133(4):e

2 Types of Heart Failure Heart Failure Pathophysiology Classification Other Nomenclature LVEF Heart failure with reduced ejection fraction (HFrEF)* Systolic HF 40% Heart failure with preserved ejective fraction (HFpEF) Recovered or improved N/A > 40% HFpEF, borderline Diastolic HF 41-49% HFpEF Diastolic HF 50% *RCTs demonstrating efficacious therapies mostly enrolled patients with EF 35% or 40% Adapted from Yancy CW, et al. Circulation. 2013;128(16):e240 e327. From N Engl J Med, Schrier RW, Abraham WT, Hormones and hemodynamics in heart failure, 241, Copyright (1999) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Heart Failure Pathophysiology Hemodynamic Model Remodeling - Afterload ventricular hypertrophy - Preload ventricular dilation Contractility - Contractility Afterload and Preload Cycle perpetuates Neurohormonal Model Angiotensin II, aldosterone Apoptosis, oxidative stress, inflammation, fibrosis, insulin resistance, baroreceptor dysfunction Norepinephrine/epinephrine Apoptosis, necrosis Vasopressin Collagen deposition Parker RB, et al. Chronic Heart Failure. In: DiPiro JT et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 9 th ed. New York, NY: McGraw-Hill; Treatment of HFrEF Goals of Therapy Symptoms need to be controlled Prevent hospitalization and reduce mortality Provide optimal patient education Optimize guideline-based pharmacotherapies Yancy CW, et al. Circulation. 2013;128(16):e240 e327. Stages of Heart Failure & Functional Classification Heart Failure Stages Stage A - At risk for HF, no structural disease or symptoms Stage B - Structural heart disease, no signs or symptoms of HF Stage C - Structural heart disease with prior/current symptoms of HF Stage D - Refractory HF requiring specialized interventions Yancy CW, et al. J Am Coll Cardiol. 2013; 62(16):e NYHA Functional Classification Class I - Asymptomatic with normal activity Class II - Comfortable at rest, symptoms with normal activity Class III - Comfortable at rest, symptoms with less than normal activity Class IV - Symptoms at rest Guideline-Directed Medical Therapy (GDMT) for Heart Failure Asymptomatic (Stage B) ACE inhibitor (ACEI) OR ARB (if intolerant to ACEI) Beta-blocker (BB) ACE = angiotensin converting enzyme ARB = angiotensin receptor blocker LOE = level of evidence SDN = isosorbide dinitrate CKD = chronic kidney disease PLUS Class I, LOE A Yancy CW, et al. J Am Coll Cardiol. 2013; 62(16):e Symptomatic (Stage C & D) African American, NYHA III/IV Add ISDN/Hydralazine Class I, LOE A NYHA II-IV, no CKD IV/V Add mineralocorticoid receptor antagonist (MRA) Class I, LOE A Diuretics: Class I, LOE C Digoxin: Class IIa, LOE B 2

3 EMERGING TREATMENTS FOR HF: SACUBITRIL/VALSARTAN WHERE DOES IT FIT IN? Angiotensin Receptor-Neprilysin Inhibitor (ARNI) Mechanism of Action: Sacubitril/Valsartan Sacubitril/valsartan Sacubitril (AHU377) (prodrug) Enzymatic cleavage LBQ657 Valsartan Neprilysin inhibition AT1 = angiotensin type 1 Vardeny O, et al. Clin Pharmacol Ther. 2013; 94(4): AT1 receptor blockade Mechanism of Action: Sacubitril/Valsartan Valsartan Angiotensin I Angiotensin II Vasoconstriction Aldosterone ACE Na/H 2 O reabsorption Vardeny O, et al. Clin Pharmacol Ther. 2013; 94(4): Bradykinin Inactive Benefits of ARBs Increased ANP, BNP & other vasodilators Neprilysin Atrial stretch Sacubitril Vasodilation Adrenomedullin ANP BNP Substance P ANP = atrial natriuretic peptide BNP = B-type natriuretic peptide PARADIGM HF Trial Design Adults with LVEF 35-40% NYHA class II-IV symptoms BNP 150 pg/ml or NT-proBNP 600 pg/ml or HF hospitalization in last 12 months ACEI or ARB x 4 weeks egfr 30 ml/min/m 2 Single-blind enalapril 10 mg BID x 2 weeks Single-blind sacubitril/valsartan mg BID x 4-6 weeks Enalapril 10 mg BID NT-proBNP = N-terminal pro BNP McMurray JJ, et al. N Engl J Med. 2014;371(11): Enalapril n = 8,442 washout x 1 day Sacubitril/valsartan 200 mg BID Sacubitril/Valsartan: Guideline Recommendations COR LOE ACC/AHA/HFSA Recommendation I ACEI: A The clinical strategy of inhibition of the RAAS with ACEIs or ARBs or ARNI, in conjunction with evidencebased ARB: A BBs and MRAs in selected patients, is recommended in patients with chronic HFrEF to reduce morbidity and mortality. ARNI: B-R I ARNI: B-R In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality. III:Harm B-R ARNI should not be administered concomitantly with ACEIs or within 36 hours of the last dose of an ACEI. III:Harm C-EO ARNI should not be administered to patients with a history of angioedema. ESC Recommendation I B Sacubitril/valsartan is recommended as a replacement for an ACEI to further reduce the risk of HF hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with ACEI, BB and MRA B-R = randomized C-EO = expert opinion Yancy CW, et al. J Am Coll Cardiol. 2016;68(13): ; Ponikowski P, et al. Eur Heart J. 2016; 37(27): Sacubitril/Valsartan FDA Indication indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction usually administered in conjunction with other heart failure therapies, in place of an ACEI or other ARB Entresto [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp.;

4 Sacubitril/Valsartan Doses for HFrEF Patient Population Initial Dose Target Dose (Maximum) Most patients 49/51 mg BID 97/103 mg BID Special populations Not on ACEI or ARB On low doses of ACEI or ARB egfr <30 ml/min/1.73 m 2 Moderate hepatic impairment 24/26 mg BID 97/103 mg BID Do NOT administer within 36 hours of ACEI administration Double dose every 2-4 weeks, as tolerated, to target dose Entresto [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; PARADIGM HF Trial Design Adults with left LVEF 35-40% NYHA class II-IV symptoms BNP 150 pg/ml or NT-proBNP 600 pg/ml or HF hospitalization in last 12 months ACEI or ARB x 4 weeks egfr 30 ml/min/m 2 Single-blind enalapril 10 mg BID x 2 weeks Enalapril washout x 1 day Single-blind sacubitril/valsartan mg BID x 4-6 weeks Enalapril 10 mg BID Sacubitril/valsartan 200 mg BID McMurray JJ, et al. N Engl J Med. 2014;371(11): Sacubitril/Valsartan FDA Indicate vs Post-Marketing Selection of Patients 80% 60% 40% 20% 0% Sacubitril/valsartan Patients by Eligibility/Usage Criteria Criteria met FDA label PARADIGM-HF FDA label, not PARADIGM Perez A, et al. J Am Coll Cardiol. 2016; 67(13_S):1546[abstract]. FDA label-not PARADIGM-HF vs PARADIGM-HF criteria Significantly sicker population FDA indication + egfr <30 ml/min (n = 19) HF readmission 4-fold higher *Women & African Americans have higher prevalence of ACEI-induced angioedema PARADIGM-HF Who Was & Was Not Studied? Characteristic Sacubitril/valsartan (n = 4187) Female gender (%)* Race (%) White Black* Asian Other Region (%) North America Latin America Western Europe Central Europe Asia-Pacific Enalapril (n = 4212) McMurray JJ, et al. N Engl J Med. 2014;371(11): ; Campo P, et al. Curr Opin Allergy Clin Immunol. 2013;13(4): EMERGING TREATMENTS FOR HF: IVABRADINE WHERE DOES IT FIT IN? Mechanism of Action: Ivabradine Long-lasting calcium current I CaL Ivabradine I f SA node AV node His-Purkinje System Transient calcium current I CaT Decreases HR No effect on contractility or blood pressure Ventricular contraction I f = hyperpolarization-activated, cyclic nucleotide-gated current, funny current DiFrancesco D, et al. Drugs. 2004;64(16): ; Hanigan S, et al. J Pharm Pract. 2016;29(1):

5 SHIFT Design Stable HF (NYHA II-IV) LVEF 35% Prospective, randomized, double-blind, placebo controlled Normal sinus rhythm (NSR), resting heart rate (rhr) 70 bpm trial Stable GDMT, including maximum tolerated beta-blocker Hospitalization for worsening HF in prior 12 months Ivabradine 5 mg BID Titrated q2 weeks to target HR bpm Placebo Primary endpoint: CV death or hospitalization for worsening HF Swedberg K, et al. Lancet. 2010;376(9744): N = 6558 SHIFT Selected Adverse Events Ivabradine Placebo P value n = 3232, n (%) n = 3260, n (%) All serious adverse events (AEs) 1450 (45%) 1553 (48%).025 All adverse events 2439 (75%) 2423 (74%).303 Heart failure 804 (25%) 937 (29%).0005 Symptomatic bradycardia 150 (5%) 32 (1%) <.0001 Asymptomatic bradycardia 184 (6%) 48 (1%) <.0001 Atrial fibrillation 306 (9%) 251 (8%).012 Blurred vision 17 (1%) 7 (<1%).042 Phosphenes 89 (3%) 17 (1%) <.0001 Swedberg K, et al. Lancet. 2010;376(9744): Ivabradine: Guideline Recommendations COR LOE ACC/AHA/HFSA Recommendation IIa B-R Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF 35%) who are receiving GDMT, including a BB at maximum tolerated dose, and who are in sinus rhythm with a HR 70 bpm at rest. ESC Recommendation IIa B Ivabradine should be considered to reduce the risk of HF hospitalization and cardiovascular death in symptomatic patients with LVEF 35%, in sinus rhythm and a resting HR 70 bpm who are unable to tolerate or have contraindications for a beta-blocker. Patients should also receive an ACEI (or ARB) and an MRA (or ARB) Generic Name Ivabradine 5 mg BID Ivabradine Doses for HFrEF Starting Dose Target Dose Maximum Dose Reduce to 2.5 mg BID if HR <50 bpm or symptomatic bradycardia Resting HR bpm 7.5 mg BID After 2 weeks of treatment, adjust dose based on heart rate In patients with conduction defects or in whom bradycardia could lead to hemodynamic compromise, initiate dosing at 2.5 mg twice daily Yancy CW, et al. J Am Coll Cardiol. 2016;68(13): ; Ponikowski P, et al. Eur Heart J 2016;37(27): Corlanor [prescribing information]. Thousand Oaks, CA: Amgen Inc.; 2015 Apr. Ivabradine Drug Interactions Metabolism CYP3A4 80% of clearance Contraindication Strong CYP3A4 inhibitors Avoid CYP3A4 inducers Moderate CYP3A4 inhibitors Strong CYP3A4 inhibitors Clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, protease inhibitors Moderate CYP3A4 inhibitors Aprepitant, cimetidine, ciprofloxacin, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, verapamil, grapefruit juice CYP3A4 inducers Carbamazepine, efavirenz, phenobarbital, phenytoin, primidone, rifampin, rifapentine, St. John s wort Corlanor [prescribing information]. Thousand Oaks, CA: Amgen Inc.; 2015.; FDA. Accessed January 23, SHIFT Design Stable HF (NYHA II-IV) LVEF 35% Prospective, randomized, double-blind, placebo controlled NSR, rhr 70 bpm trial Stable GDMT, including maximum tolerated beta-blocker Hospitalization for worsening HF in prior 12 months Ivabradine 5 mg BID Titrated q2 weeks to target HR bpm n = 6558 Placebo Primary endpoint: CV death or hospitalization for worsening HF Swedberg K, et al. Lancet. 2010;376(9744):

6 SHIFT: Maximally Tolerated Beta-blockade? Characteristic SHIFT Ivabradine (n = 3241) Placebo (n = 3264) Blood pressure (mmhg) 122/76 121/76 132/75 Heart rate (bpm) Cardiac glycoside/digoxin at baseline (%) 22% 22% 30% BB at baseline (%) Mean daily dose of BB (mg) Bisoprolol Carvedilol Metoprolol succinate 6 ± 3 25 ± ± 60 6 ± 3 25 ± ± 60 OPTIMIZE-HF BB continued (n = 1350) n/a 21 ± ± 52 SHIFT: Reserve Ivabradine for Higher HR? Baseline HR < 77 bpm (n = 3144) 77 bpm (n = 3357) P = Favors ivabradine Favors placebo Swedberg K, et al. Lancet (9744): ; Fonarow GC, et al. Am J Cardiol. 2008;102(11): Swedberg K, et al. Lancet. 2010; 376(9744): GDMT for Heart Failure: Updated Asymptomatic (Stage B, Class I) ACE inhibitor OR ARB (if intolerant to ACEI) OR Sacubitril/valsartan? PLUS Beta-blocker Symptomatic (Stage C, Class II-IV) African American, Class III/IV Add ISDN/Hydralazine Class II-IV Sacubitril/valsartan (ACEI/ARB naïve)? Replace ACEI/ARB with sacubitril/valsartan Add MRA Diuretics Ivabradine Digoxin Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e ; Yancy CW, et al. J Am Coll Cardiol. 2016;68(13): ; Ponikowski P, et al. Eur Heart J. 2016;37(27): Hierarchy of GDMT for Heart Failure IIa I Class of Recommendation + Digoxin + Ivabradine + Diuretics Sacubitril/valsartan Level of Evidence + MRAs+/- Nitrates/Hydralazine ACEI or ARBs + BBs C B A Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e ; Yancy CW, et al. J Am Coll Cardiol. 2016;pii:S (16) Use Evidence-Based Heart Failure Medications Initiate at low doses Titrate to target dose, not therapeutic response Dosing tables provided in appendix Renal function threshold for inclusion in anti-raas trials Creatinine ~ mg/dl egfr <30 ml/min/1.73 m 2 RAAS = renin angiotensin aldosterone system egfr = estimated glomerular filtration rate Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e Monitoring Vital signs & symptoms ACE inhibitors & ARBs Potassium & renal function Within 1-2 weeks MRAs Potassium & renal function Within 2-3 days, then At 7 days, then Every month x 3, then Every 3 months Education!!! Patient Case: JA 63 year-old African American female presents for outpatient follow up She was diagnosed with HFrEF during hospitalization for acute heart failure 2 months ago Since that time, her symptoms are stable but still present 6

7 PMH HFrEF Hypertension Diabetes Dyslipidemia Chronic kidney disease Medications Lisinopril 20 mg daily Carvedilol 12.5 mg BID Bumetanide 1 mg BID Atorvastatin 80 mg daily Insulin glargine 20 units/day PMH = past medical history PPO = preferred provider organization Patient Case: JA Vital signs BP 116/78 mmhg HR 54 bpm Echocardiogram LVEF 25% (2 months ago) Labs Sodium 134 meq/l Potassium 4.3 meq/l Creatinine 2.3 mg/dl egfr ~25 ml/min/1.73m 2 Insurance: PPO 65 year-old Caucasian male is referred from the local community hospital for advanced therapy work-up He was diagnosed with HFrEF 2 years ago, and had 2 HF hospitalizations within the past 6 months Since his diagnosis, RS has experienced a progressive decline in his functional status and admits to reduced mood given ADL limitations ADL = activities of daily living Patient Case: RS Patient Case: RS PMH HFrEF Chronic obstructive pulmonary disease (COPD) Smoking Medications Furosemide 40 mg BID Enalapril 2.5 mg BID Metoprolol L 50 mg daily Fluticasone/salmeterol 500 mcg/50 mcg BID Tiotropium 18 mcg daily Varenicline 1 mg BID Vital signs BP 92/58 mmhg HR 95 bpm Echocardiogram LVEF 20-25% (8/16) Labs Sodium 127 meq/l Potassium 4.7 meq/l Creatinine 1.7 mg/dl egfr ~60 ml/min/1.73m 2 Insurance: Medicare Advantage TRANSITIONS OF CARE AND IMPACT OF CORE MEASURES HF Readmissions & TOC What s All the Fuss About? 30-day readmission & mortality (risk-standardized) Added to CMS core measures & publicly reported since 2007 Acute myocardial infarction (AMI) HF Affordable Care Act (2010) Rewards hospitals with incentive payments for high-quality care All hospitals have base diagnosisrelated group (DRG) payments reduced each year Fiscal Year 2017 and beyond: 2% Funds incentive payments to highperforming hospitals Clinical Care Process Measures and Patient Experience of Care (HCAHPS) CMS. Accessed March 12, 2017.; CMS. Accessed March 10, Gaps in Care Transitions Poor Education, Low Health Literacy, or Both? Acute Coronary Syndrome Lack of awareness regarding information from index admission for AMI Only 41% aware of AMI diagnosis 67% could recall lifestyle modifications Top 3 areas for improvement with educational information identified by patients post-mi Follow-up after discharge Medication information Examinations Patient & Caregiver Concerns Patient Poor face-to-face education, simply given packet to read Medication cost is a barrier Contacting providers is challenging Caregiver Not involved in educational process at discharge Patient is not ready for discharge Patient refuses to seek care after discharge Sanderson BK, et al. J Healthc Qual ; Oterhals K, et al. Eur J Cardiovasc Nurs. 2006;5(4): ; Ursan ID, et al. J Health Care Poor Underserved. 2016;27(1):

8 Improving Transitions of Care (TOC) ACCP White Paper on Pharmacist Roles 1. Medication reconciliation during care transitions 2. Participate in rounds 3. Patient & caregiver education 4. Participate in discharge Discharge patient interviews Follow up on drug-related problems Assess and address adherence issues Post-discharge follow-up within 2-4 days LTCF = long-term care facility Hume AL et al. Pharmacotherapy. 2012;32(11):e Consultant pharmacists med rec in LTCF & assisted living 6. Community pharmacists Clarify discrepancies & review auto refills post-discharge 7. Ambulatory care pharmacists 8. Home health care 9. Medically underserved and homeless Services to address adherence, access, & health literacy Pharmacist TOC Programs in Heart Failure Studied Countries 7 studies US UK Australia Ireland Providers Pharmacist (n = 5) Pharmacist + nurse (n = 2) Ponniah A, et al. J Clin Pharm Ther. 2007;32(4): Types of Interventions (may have included 1 of the following) Patient education Postdischarge call counseling Identification/resolution of risk factors for readmission Evaluation and/or optimization of drug therapy Contacted community pharmacists & physicians Home visit at 1 week Home-based intensive counseling Jadad scores 2 for all studies, indicating potential for bias Outcome Adherence Exercise capacity / Readmits HF readmits Clinical events Mortality Key Components of Successful TOC Programs Study Collaborative with Other Providers Med History (Med Rec) EBM Ix with Physician Patient Education Med Adherence Varma Phone Follow-up Gattis Rainville Gwadry- Sridhar Lopez Cabezas (multidisciplinary) Gunadi Walker EBM = evidence-based medicine Ix = intervention Gwadry-Sridhar FH, et al. Am Heart J. 2005;150(5):982.; Varma S, et al. Pharmacotherapy (7):860-9.;Gattis WA, et al. Arch Intern Med. 1999;159(16): ; Rainville EC, et al. Am J Health Syst Pharm. 1999;56(13): ; Gunadi S, et al. Am J Health Syst Pharm. 2015;72(13): ; Lopez Cabezas C, et al. Farm Hosp. 2006;30(6): ; Walker PC, et al. Arch Intern Med 2009;169(21): Conclusion New HF therapies improve outcomes vs standard care Sacubitril/valsartan: CV death & HF hospitalization vs ACEIs Ivabradine: HF hospitalization vs standard care Some uncertainty exists regarding place in therapy for new HF therapies in selected patients Opportunity to optimize GDMT for patients with HFrEF Pharmacists can play a key role in optimizing HF therapy for patients with HFrEF across settings, including transitions of care Additional Resources Heart Failure Guidelines Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e Yancy CW, et al. J Am Coll Cardiol. 2016;68(13): Ponikowski P, et al. Eur Heart J. 2016;37(27): Review Articles Vardeny O, et al. Clin Pharmacol Ther. 2013; 94(4): DiFrancesco D, et al. Drugs. 2004;64(16): Hanigan S, et al. J Pharm Pract. 2016;29(1): Transitions of Care Hume AL, et al. Pharmacotherapy. 2012;32(11):e Ponniah A et al. J Clin Pharm Ther. 2007;32(4): Landmark Clinical Trials McMurray JJ, et al. N Engl J Med. 2014;371(11): Swedberg K, et al. Lancet. 2010;37(9744)6: Package Inserts pharma.us.novartis.com/files/entresto.pdf tes/pi-amgencom/corlanor/corlanor_pi_hcp.ashx Patient Assistance Programs 8