Pharmacologic Considerations for Reducing Hospital Readmission in Geriatric Patients with Heart Failure Barbara J. Zarowitz, Pharm.D. Chief Clinical Officer, Vice President of Clinical Services Omnicare, Inc., and Adjunct Professor of Pharmacy Practice College of Pharmacy and Health Sciences Wayne State University November 2013 Objectives To identify the key pathophysiologic mechanisms operative in patients with heart failure; To differentiate characteristics of heart failure in persons older than 80 years of age compared to younger patients; To select strategies of heart failure management recommended in current evidence-based guideline; To identify pharmacokinetic and pharmacodynamics features of older persons with heart failure; To determine important pharmacologic considerations of heart failure medications in older persons; To select the most common reasons for readmission of heart failure patients to the hospital and strategies to mitigate the risk of rehospitalization; and Using a case-based approach, to select appropriate interventions to optimize the care of older patients with heart failure. Heart Failure Clinical Program © Omnicare, Inc. 2013 2 Disclosures Dr. Zarowitz is an employee of Omnicare, Inc., and holds Omnicare stock She has been awarded numerous research grants for Omnicare Senior Health Outcomes from: AbbVie Amgen Astellas Avanir GlaxoSmithKline Mylan Optimer Sanofi-aventis Savient Case Presentation 83 year old Caucasian male, Clcr 63 mL/min, dry weight of 160 lb (72.2 kg) who presented to the nurse practitioner with complaints of shortness of breath and productive coughing for the last 4 weeks BP-90/64, HR-100, RR-20, T98.6 PMH: NYHA stage IV HF, glaucoma, coronary artery disease, hypertension, ocular strokes HPI: hospitalized the previous year twice for syncope associated with heart failure. Cardiac arrest during one hospitalization following administration of ramipril 2.5 mg CXR: no infiltrates Labs: WBC – wnl Medication aspirin EC clopidogrel furosemide metoprolol mirtazapine zolpidem simvastatin spironolactone digoxin Vitamin D3 Vitamin E latanoprost furosemide Dose 81 mg 75 mg 40 mg 50 mg 30 mg 5 mg 40 mg 25 mg 0.0625 mg 1,000 units (2 tabs) 400 units 1 drop each eye 40 mg 40 mg 40 mg (2 tabs) 40 mg (2 tabs) 40 mg (4 tabs) Frequency once daily once daily once daily twice daily at bedtime at bedtime at bedtime once daily once daily once daily once daily at bedtime wt ≤ 162 = no dose wt 163 - 167, 1 tab wt 168, 2 tabs wt 169, 2 tabs twice daily wt 170, 2 tabs twice daily Heart Failure Pathophysiology What is Heart Failure? 6 Definition of HF • Inability of the heart to pump blood to the body sufficient to meet the body’s demands • Results from structural or functional cardiac disorder – Impaired ability of the ventricle to fill with or eject blood © Omnicare, Inc. 2013 7 7 Pathophysiology of Heart Failure Causal Factors Myocardial Damage Myocardial Failure Cardiac output LV end diastolic pressure SVR (afterload) Blood Volume (preload) Compensatory Responses RAA SNS ANF Vasopressin Pumping and Filling Problems and Heart Failure NORMAL SYSTOLIC DYSFUNCTION DIASTOLIC DYSFUNCTION Diastole (Filling) The ventricles fill normally with blood The enlarged ventricles fill with blood The stiff ventricles fill with less blood than normal Systole (Pumping) The ventricles pump out ~60% of the blood © Omnicare, Inc. 2013 The ventricles pump out less than 40-50% of the blood The ventricles pump out ~60% of the blood, but the amount may be lower than normal 9 Facts About Heart Failure (HF) (continued) Prevalence of HF in nursing homes (NHs) is ~20% HF is the 2nd most preventable cause of emergency department (ED) visits (19%) 668,000 ED visits and 1,094,000 hospital discharges in 2009 Discharges to someplace other than home have tripled in the past decade 50% of Medicare patients discharged to NHs are rehospitalized within 6 months Characteristics associated with a high risk for rehospitalization with HF Higher NYHA stage Greater functional limitations (ADLs) Concomitant psychosis Concomitant renal failure © Omnicare, Inc. 2013 10 Roger VL et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation. 2012;125:e2–e220. Hutt E et al. J Am Med Dir Assoc 2011; 12:595-601 10 Facts About Heart Failure (HF) In 2008, 1 in 9 death certificates in the U.S. mentioned HF An estimated 6.6 million US adults have HF 60-79 years-old: 9% of men and 5.4% of women 80+ years-old: 11.5% of men and 11.6% of women 75% of HF cases had HTN prior to their HF Lifetime risk for HF is double for those with BP >160/90 mmHg compared to <140/90 More common in the African American population More common in men than women Roger VL et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation. 2012;125:e2–e220. 11 © Omnicare, Inc. 2013 Heart Failure in the Elderly Persons older than 65 years account for 80% of heart failure hospitalizations Prevalence doubles with each decade of life over age 75 About 6% to 10% over 65 years have heart failure 88% of newly diagnosed cases occur in patients older than 65 years 49% are older than 80 years Features Distinguishing Heart Failure in the Elderly from Heart Failure Occurring During Middle Age Middle Age Elderly (≥ 65 years) Prevalence <1% ≈10% Gender M>F F>M Etiology Coronary artery disease Hypertension Reduced Normal Comorbidities Few Multiple RCTs Many Few Evidence-based Empiric Cardiologist Primary care LVEF Therapy Physician M=male; F=female; LVEF=left ventricular ejection fraction; RCT=randomized clinical trial Adapted from Rich RW. Drug therapy for heart failure in the elderly. Am J Ger Cardiol 2003;12:235-42. Pharmacokinetic and Pharmacodynamic Variants in Older Persons with Heart Failure Absorption Increased gastric pH, delayed gastric emptying, reduced GI blood flow and slowed intestinal transit Decreased bioavailability of medications with aciddependent absorption (iron) and slowed absorption of medications, especially those that are enteric coated Metabolism 20 – 30% reduction in liver mass and hepatic blood flow but hepatocytes remain intact CYP isozymes may be decreased but do not necessarily result in reduced clearance first-pass metabolism is reduced with age Elimination Clcr declines progressively with age- 0.75 mL/min/year 14 Underlying Causes of Heart Failure Coronary Artery Disease Cardiovascular disease Valvular Heart Disease Infections Alcohol Heart Failure Hypertension Radiation Drugs Tachycardia Neuromuscular disease Connective tissue disease Nutritional and metabolic disorders © Omnicare, Inc. 2013 15 Selected Risk Factors for Heart Failure Unmodifiable Treatable Myocardial infarction Kidney disease Non-white race Family history Male sex Age Sleep disordered breathing Heart disease Hyperlipidemia HYPERTENSION Smoking Valve disease Obesity/Diet Diabetes Physical inactivity AFib Alcohol consumption Mental stress Depression Modifiable © Omnicare, Inc. 2013 Kenchaiah S et al. Med Clin N Amer 2004:88;1145-72. 16 Risk Factors for Heart Failure Strongly and consistently associated with HF Less consistently associated with HF Age Male sex Hypertension Electrocardiographic LV hypertrophy Myocardial infarction Diabetes Valve disease Overweight/obesity Excessive alcohol consumption Smoking Dyslipidemia Renal insufficiency Sleep-disordered breathing Low physical activity Low socioeconomic status Coffee consumption Dietary sodium intake Increased heart rate Impaired pulmonary function Mental stress and depression Kenchaiah S et al. Med Clin N Amer 2004:88;1145-72. Medications That May Exacerbate Heart Failure Agents Antiarrhythmic agents (avoid disopyramide and flecanide; amiodarone and dofetilide are acceptable, if necessary, for arrhythmia) Calcium channel antagonists (diltiazem, verapamil) Itraconazole Terbinafine Alcohol (excessive amounts in predisposed patients) Doxorubicin Daunomycin Cyclophosphamide Androgens COX-2 inhibitors Estrogens Glucocorticoids Nonsteroidal anti-inflammatory drugs Salicylates (high doses) Sodium-containing drugs (e.g., ticarcillin) Thiazolidinediones (rosiglitazone, pioglitazone) Albumin Blood products Rationale Negative inotropic effects Cardiotoxic Sodium and water retention Osmotic agents Signs and Symptoms of Heart Failure SIGNS Tachycardia Cachexia and muscle wasting Third heart sound Positive hepatojugular reflux Bilateral rales Peripheral edema Laterally displaced apical pulse Elevated jugular venous distension Unexpected weight gain SYMPTOMS • Shortness of breath • Orthopnea • Paroxysmal nocturnal dyspnea • Reduced exercise tolerance • Lethargy, fatigue • Unexplained cough • Wheeze • Edema • Loss of appetite • Change in urine production Congestive Heart Failure 20 The FACES of Heart Failure • Fatigue • Activities limited • Chest congestion • Edema or ankle swelling • Shortness of breath HFSA. Who is the patient with heart failure? 2002. Available at: http://www.hfsa.org/pdf/faces_card.pdf © Omnicare, Inc. 2013 21 21 BNP (B-type natriuretic peptide) Released in response to pressure overload Should be measured in patients being evaluated for dyspnea in which the contribution of HF is unknown Generally as BNP increases, HF worsens, and as HF is successfully treated, BNP decreases May also be elevated in acute MI, PE, COPD, older age, female gender and renal impairment © Omnicare, Inc. 2013 BNP (pg/mL) Interpretation <100 Reliably rules out HF 100-399 Possible HF (~75% of cases are HF) >400 Suggestive of HF 22 BNP Diagnostic Algorithm Dyspnea Physical Examination, Chest XR, ECG, BNP Level BNP <100pg/ml BNP 100-400 pg/ml BNP >400pg/ml Baseline LV Dysfunction, Underlying Cor Pulmonale, Or Acute Pulmonary Embolism CHF Very Unlikely (2%) Yes No Possible Exacerbation of CHF (25%) CHF Likely (75%) Adapted from: Tabbibizar R, Maisel A. Curr Opin Cardiol. 2002;17:343. CHF Very Likely (95%) BNP for Diagnosis BNP Concentration (pg/ml) BNP concentration for the degree of heart failure severity 2500 2013 + 266 2000 1500 791 + 165 1000 500 186 + 22 0 Mild n = 27 Maisel A et al. J Am Coll Cardiol 2001;37(2)379-85. Moderate n = 34 Severe n = 36 Evidence-Based Treatment Guidelines Yancy CW, et al. 2013 ACCF/AHA Heart Failure Guidelines http://content.onlinejacc.org Jessup M, et al. 2009 ACCF/AHA guidelines for the diagnosis and management of heart failure in adults. Circulation. 2009;119:1977–2016. 25 Heart Failure with Reduced EF Treatment Approaches for Heart Failure 27 Goals of Treatment Survival Exercise capacity Quality of life Morbidity Progression of disease Symptoms © Omnicare, Inc. 2013 28 Approach to Treatment Diagnose and Stage HF Establish patient-centered goals (e.g., BP) Utilize non-pharmacological interventions and evidence-based medications Titrate and maximize doses as tolerated Monitor with vigilance Dietary considerations Changes in signs and symptoms (e.g., weight gain) Medication monitoring (e.g., BMP, pulse, etc) 29 © Omnicare, Inc. 2013 Classification of HF ACC/AHA Heart Failure Stage A NYHA Functional Class At high risk for HF, but without structural heart disease or symptoms of HF (e.g., HTN, CAD) Not applicable B Structural heart disease but without symptoms of HF I With cardiac disease but asymptomatic and without limitations of physical activity C Structural heart disease with prior or current symptoms of HF II Symptomatic with ordinary exertion resulting in slight limitation of physical activity (mild HF) III Symptomatic with less than ordinary exertion resulting in marked limitations of physical activity (moderate HF) IV Symptomatic at rest resulting in inability to carry on any physical activity without discomfort (severe HF) D Refractory HF requiring specialized interventions © Omnicare, Inc. 2013 30 Medications That May Cause or Exacerbate HF* Agents How they cause/exacerbate HF Antiarrhythmics† [e.g., Multaq (dronedarone), Rythmol (propafenone), Tambocor (flecanide)] Non-dihydropyridine Calcium Channel Blockers [e.g., Calan or Isoptin (verapamil) or Cardizem (diltiazem)] Itraconazole or Terbinafine Negative inotropic effects (decrease the force of the hearts contraction) Alcohol (excessive amounts) Some chemotherapy treatments (e.g., doxorubicin, daunomycin, cyclophosphamide) Cardiotoxic Androgens or Estrogens Aspirin (high doses) NSAIDs (e.g., celecoxib, ibuprofen, meloxicam, naproxen) Glucocorticoids (e.g., prednisone) Thiazolidinediones [e.g., pioglitazone, Avandia (rosiglitazone)] Sodium and water retention Albumin Blood products (e.g., transfusion) Osmotic agents Avoid or minimize use whenever possible. Monitor closely if must be used. * - not all inclusive † - amiodarone or Tikosyn (dofetilide) are acceptable alternatives if necessary for arrhythmias 31 Non-Pharmacological Therapies Modifiable risk reduction (e.g., smoking cessation, stress management) Dietary modifications Low sodium, low saturated fat diet Limit caffeine intake Limit alcohol intake Encourage weight loss if BMI > 25 Closely watch fluid intake Encourage physical activity as tolerated 32 © Omnicare, Inc. 2013 Pharmacological Therapies Commonly Used ACE Inhibitors (e.g., lisinopril) Angiotensin Receptor Blockers [ARBs (e.g., losartan, valsartan) Beta Blockers (e.g., metoprolol, carvedilol) Diuretics Digoxin Aldosterone Antagonists (e.g., spironolactone, eplerenone) Hydralazine + Isosorbide ACCF/AHA Guidelines: “It is recommended that evidence-based therapy for HF be used in the elderly patient, with individualized consideration of the elderly patient’s altered ability to metabolize or tolerate standard medications” 33 © Omnicare, Inc. 2013 Yancy CW, et al. 2013 ACCF/AHA Heart Failure Guidelines ACE Inhibitors (ACEIs) (e.g., lisinopril, enalapril) Associated with a significant decrease in mortality “recommended for all patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated” Lower blood pressure by causing blood vessels to relax and expand and by reducing sodium and water retention Monitor for: Hypotension Persistent dry cough (~20%) Angioedema (<1%) Elevated potassium Elevated serum creatinine Jessup M, et al. 2009 ACCF/AHA Guidelines. Circulation. 2009;119:1977–2016. Yancy CW, et al. 2013 ACCF/AHA Guidelines. http://content.onlinejacc.org 34 © Omnicare, Inc. 2013 ACE-I: Mechanism of Action VASOCONSTRICTION ALDOSTERONE VASOPRESSIN SYMPATHETIC VASODILATATION PROSTAGLANDINS Kininogen tPA Kallikrein Angiotensinogen RENIN Angiotensin I A.C.E. ANGIOTENSIN II Inhibitor BRADYKININ Kininase II Inactive Fragments ACE Inhibitors RISKS Hypotension Renal dysfunction Hyperkalemia Cough Angioedema Neutropenia * Not an indication for all ACEIs BENEFITS Prolonged survival* Clinical improvement More stable clinical course Fewer hospitalizations Slower disease progression ACE Inhibitors: Indications and Doses INDICATION HF LV Dysfunction Initial Dose Maximum Dose captopril (Capoten®) (post-MI) 6.25 mg tid 50 mg tid enalapril (Vasotec®) (asymptomatic) 2.5 mg bid 10 – 20 mg bid fosinopril (Monopril®) NA 5 - 10 mg qd 40 mg qd lisinopril (Prinivil®, Zestril®) NA 2.5 - 5 mg qd 20 – 40 mg bid quinapril (Accupril®) NA 10 mg bid 40 mg bid ramipril (Altace®) (post-MI) 1.25 – 2.5mg qd 10 mg qd trandolapril (Mavik®) (post-MI) 1 mg qd 4 mg qd Agent ACE = angiotensin-converting enzyme, LV = left ventricular HF = heart failure, MI = myocardial infarction ACE Inhibitors, Heart Failure, and Mortality Reduction STUDY ACE-I CONSENSUS Enalapril 2.5-40 mg/d vs. placebo N=253 Class IV HF 12 months 6 month mortality ↓ 40% 1 year mortality ↓ 31% Death from progressive HF ↓ 50% Enalapril 10 mg bid vs. placebo N=2,589 EF < 35% 42 months 3.5 year mortality ↓ 16% Death or CHF hospitalization ↓26% CV hospitalization ↓ 10% Ramipril 2.5-5 mg bid N=2,006 HF post MI 30 months All cause mortality ↓ 17% Risk of 1st event ↓ 19% Captopril 12.5-150 mg/d vs. placebo N=2,231 EF < 40% Post MI 42 months All cause mortality ↓ 19% CV death ↓ 21% CHF development ↓ 37% Recurrent MI ↓ 25% Mean age 71 SOLVD Mean age 60 AIRE Mean age 65 SAVE Patients Duration Results ATLAS Trial Low-dose vs. high dose lisinopril 2.5 to 5 mg QD or 32.5 to 35 mg qd N = 3,164 Average age 63.6 years NYHA II-IV EF ≤ 30% High dose group had: 12% lower risk of death or hospitalization for any reason (P=0.002) for high 24% fewer hospitalizations for heart failure (P=0.002) Risk of death reduced 8% in the high dose group (P=0.128) Packer M et al. Circulation 1999;100:2312-8. CONSENSUS Trial Probability of death 0.8 Placebo 0.7 0.6 p< 0.001 0.5 p< 0.002 0.4 Enalapril 0.3 0.2 0.1 0 0 1 2 3 4 5 6 7 Months CONSENSUS. N Engl J Med 1987;316:1429-35. 8 9 10 11 12 SOLVD Trial (Treatment Arm) 0.8 Placebo Placebo Percent Survival 0.7 n=1284 p< 0.001 0.6 p = 0.0036 0.5 p< 0.002 0.4 Enalapril n=1285 Enalapril 0.3 0.2 n = 2589 CHF - NYHA II-III - EF < 35 0.1 0 0 6 SOLVD. N Engl J Med 1991;325:293-301. 12 18 24 Months 30 36 42 ACE Inhibitors: Contraindications/ Risk-Benefit Considerations Contraindications Known bilateral renal artery stenosis History of angioedema Pregnancy Risk-benefit considerations Systolic blood pressure < 90 mm Hg Serum creatinine > 3 mg/dL Serum potassium > 5.5 mEq/mL Angiotensin Receptor Blockers (ARBs) (e.g., losartan, valsartan) Similar benefit to ACEIs “recommended in patients with current or prior symptoms of HF and reduced LVEF who are ACE inhibitor-intolerant” Routine combined use of ACEI, ARB and aldosterone antagonist is not recommended Monitor for: 43 Hypotension Angioedema (<1%) Elevated potassium Elevated serum creatinine © Omnicare, Inc. 2013 Yancy CW, et al. 2013 ACCF/AHA Heart Failure Guidelines Jessup M, et al. 2009 ACCF/AHA guidelines Circulation. 2009;119:1977–2016. Angiotensin II Receptor Blockers (ARB): Mechanism of Action RENIN Angiotensin I Angiotensinogen ACE Other pathways ANGIOTENSIN II AT1 Receptor Blockers AT1 Vasoconstriction RECEPTORS Proliferative Action AT2 Vasodilatation Antiproliferative Action ACC/AHA Guidelines on the Role of ARBs in HF Therapy Several clinical trials with ARBs failed to show mortality benefit in heart failure ARBs should not be considered equivalent or superior to ACE inhibitors in the treatment of HF ARBs should not be used for the treatment of HF in patients who have had no prior use of an ACE inhibitor ARBs should be used in patients with angioedema or an intractable cough on an ACE-I. ARBs are as likely as ACE-I to produce hypotension, worsening renal function and hyperkalemia 2013 ACCF/AHA Heart Failure Guidelines . J Am Coll Cardiol. http://content.onlinejacc.org/ Val-HeFT: Comparison of Event Rates Valsartan (%) Placebo (%) All-cause mortality 17.3 27.1 0.67 0.017 Morbidity/ mortality 24.9 42.5 0.56 <0.001 Cardiovascular death 15.7 22.1 0.76 0.074 Sudden death with resuscitation 0.5 1.1 0.46 0.529 Hospital admission for HF 13.0 26.5 0.47 <0.001 Event Maggioni AP et al. J Am Coll Cardiol 2002;40:1414-21. RR* p CHARM Trial 3 studies in one CHARM-Alternative: LVEF ≤ 40% and could not tolerate an ACE inhibitor CHARM-Added: LVEF ≤ 40% who were currently taking an ACE inhibitor, with or without a beta-blocker CHARM-Preserved: LVEF > 40% Overall-- showed ARB beneficial in terms of morbidity and mortality in heart failure Combination of ACEI and ARB in Heart Failure Management Background Therapy N ACEI +, Beta Blocker - 3034 ACEI +, Beta Blocker + 1610 ACEI -, Beta Blocker - 228 ACEI -, Beta Blocker + 140 Relative Risk of Death 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Valsartan Better Placebo Better P=0.009 Test for heterogeneity Cohn JN et al. NEJM 2001;345:1667-75 All-Cause Mortality in the VALIANT Study All-cause mortality (%) Hazard ratio (95% CI) compared with captopril p value 19.5 - - Valsartan (n=4909) 19.9 1 (0.90-1.11) 0.98 Combination (n=4885) 19.3 0.98 (0.89-1.09) 0.73 Group Captopril (n=4909) Pfeffer MA et al. N Engl J Med 2003; 349:1893-1906. VALIANT: Cardiovascular Death, Recurrent MI, or Heart Failure Hospitalization Secondary End Point CV death, re-MI, or heart-failure hospitalization (%) Hazard ratio (95% CI) compared with captopril p value Captopril (n=4909) 31.9 - - Valsartan (n=4909) 31.1 0.95 (0.88-1.03) 0.20* Combination (n=4885) 31.1 0.97 (0.89-1.05) 0.37* Group *Not significant Pfeffer MA et al. N Engl J Med 2003; 349:1893-1906. VALIANT: Incidence of Adverse Events Any adverse event (%) Any ADE leading to permanent study drug discontinuation (%) Captopril 28.4 7.7 Valsartan 29.4 5.8* Combination 34.8* 9.0* Group * Significant difference from captopril (p<0.05) Pfeffer MA et al. N Engl J Med 2003; 349:1893-1906. Beta-Blockers (BBs) (bisoprolol, carvedilol, or metoprolol succinate XL) Prevent the speeding up of the damaged heart “recommended for all patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated” Start only if patients have stable fluid status and gradually increase the dose as tolerated Titrate no sooner than every 2 weeks May initially worsen HF and may need to adjust diuretics to maintain pretreatment weight Monitor heart rate and blood pressure Typically held if pulse <60 beats per minute Monitor for hypoglycemia if diabetic May block symptoms of hypoglycemia except sweating Carefully assess risk vs. benefit for patients with: Reactive airway disease (e.g., asthma) COPD Peripheral vascular disease 52 2013 ACCF/AHA guidelines. http://content.onlinejacc.org/ Dosages of Beta-Blockers in Heart Failure Drug Starting Dosage Titration Sequence* Maximum Dosage Bisoprolol (Zebeta®) 1.25 mg/day Increase to 2.5 mg/day in 2-4 weeks, 10 mg/day then increase to 5.0 mg/day in 2-4, weeks, then increase to maximum Carvedilol (Coreg®) 3.125 mg twice daily Metoprolol 12.5 mg/day extended release (Toprol XL®) Increase to 6.25 mg bid in 2-4 weeks, 25 mg twice then increase to 12.5 mg bid in 2-4 daily (50 mg weeks, then increase to maximum twice daily if > 85 kg) Increase to 25 mg/day in 2-4 weeks, then Increase to 50 mg/day in 2-4 weeks, then increase to 100 mg/day in 2-4 weeks, then increase to maximum 200 mg/day *Doses should only be increased if resident tolerates current dose. Some residents will not tolerate higher doses or may require slower titration. ACC/AHA Heart Failure Guidelines, 2001; Farrell MH et al. JAMA 2002;287:890-97. Diuretics (furosemide, bumetanide, hydrochlorothiazide,metolazone) Reduce fluid volume to decrease workload of the heart Loop diuretics (e.g., furosemide) are generally more effective than thiazide diuretics (e.g., hydrochlorothiazide) Thiazides are less effective with declining kidney function Assess edema and monitor weight frequently Often requires use/adjustment of potassium supplementation Monitor electrolytes and kidney function routinely Monitor for rash/photosensitivity Combination therapy with a loop and thiazide diuretic may be necessary in the presence of diuretic resistance 2013 ACCF/AHA guidelines . http://content.onlinejacc.org/ 54 Action of Diuretics Thiazides Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle CORTEX K-sparing Inhibit reabsorption of Na in distal convoluted and collecting tubule MEDULLA Loop of Henle Loop Diuretics Inhibit exchange of Cl-Na-K in thick segment of the ascending loop of Henle Collecting Tubule Loop Diuretics Mechanism of action Act on the ascending limb of loop of Henle Increase potassium, magnesium and calcium excretion More effective than thiazide diuretics Adverse reactions Electrolyte/metabolic disturbances hypokalemia, hypomagnesemia, hyperglycemia, hyperuricemia Metabolic alkalosis Azotemia Hypotension, including orthostasis Ototoxicity Other (rash, photosensitivity) Thiazide Diuretics Mechanism of action No dose response Increase potassium, magnesium and calcium excretion more than with loop diuretics Increase renal vasoconstriction Increase uric acid excretion Adverse reactions Electrolyte/metabolic disturbances hypokalemia, hypomagnesemia, hyperglycemia, hyperuricemia Metabolic alkalosis Azotemia Hypotension, including orthostasis Other (rash, photosensitivity) Torsemide Loop diuretic Consistent absorption Reduced fatigue Fewer hospitalizations Lower cost of care Murray MD, Deer MM, Ferguson JA et al. Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Am J Med. 2001;111:513-20. Diuretic Resistance: Causes Delayed absorption of the diuretic Reduced secretion of the diuretic into the tubular lumen (its site of action) Compensatory retention of sodium after the effective period of the diuretic Hypertrophy and hyperplasia of epithelial cells of the distal convoluted tubule Diuretic Resistance: Management Rule out non-compliance Dose adjustment Intravenous bolus injection or continuous infusion of a loop diuretic Combination diuretic therapy Metolazone use in combination with loops Given 30 minutes prior to loop administration Monitor closely for hypokalemia Digoxin Increases the force and velocity of cardiac contraction while also reducing the heart rate “can be beneficial in patients with current or prior symptoms of HF and reduced LVEF to decrease hospitalizations for HF” 2012 Updated Beers Criteria list 0.125 mg/day as the maximum recommended dose Monitor pulse prior to giving each dose Monitor for signs/symptoms of toxicity (nausea, anorexia, visual disturbances, electrolyte abnormalities, impaired cognition, weakness, dizziness, hallucinations, etc) Monitor BMP and digoxin concentration routinely Serum drug concentration of 0.5-0.8 ng/mL is the recommended therapeutic range 2013 ACCF/AHA guidelines. http://content.onlinejacc.org/ 61 Digoxin Inhibits sodium-potassium adenosine triphosphatase Promotes calcium influx via sodium-calcium exchange mechanism Results in an increase in the contractile state of the heart Stroke volume and cardiac output increase Indirect increase in parasympathetic tone Results in decrease in heart rate Direct and indirect decrease in sympathetic tone Secondary to impaired cardiac output Indirectly decreases sympathetic vasoconstriction Digoxin: Mechanism of Action Digoxin Na-K ATPase Na+ K+ K+ Na+ Na-Ca Exchange Na+ Myofilaments CONTRACTILITY Ca++ Ca++ Digoxin: Clinical Use Therapy is initiated at dose of 0.125 mg for heart failure Lower doses such as every other day Some elderly Impaired renal function Caution in patients with significant sinus or atrioventricular block Not indicated for stabilization of acute decompensated heart failure Serum Digoxin Concentrations Are lower digoxin concentrations effective? Methods Data from PROVED and RADIANCE Both were randomized, multi-center, double-blind clinical trials PROVED – diuretic vs. diuretic + digoxin RADIANCE – ACEI+diuretic vs. ACEI+diuretic+digoxin Compared digoxin withdrawal vs. continuation for worsening heart failure Serum drug concentration (SDCs) obtained at baseline, 4, 8, and 20 weeks Adams KF et al. J Am Coll Cardiol 2002;39:946-53. Risk of Treatment Failure Based on Randomization SDC Group Treatment Group Digoxin concentration (SDC) Relative Risk 95% CI P Value < 0.9 ng/ml 0.09 0.01-0.66 0.018 > 0.9-1.2 ng/ml 0.22 0.08-0.61 0.004 > 1.2 ng/ml 0.17 0.06-0.44 <0.001 Relative risk and p values are based on the adjusted Cox proportional hazards analysis. CI = confidence interval; SDC = serum digoxin concentration Adams KF et al. J Am Coll Cardiol 2002;39:946-53. Digoxin: Clinical Trials Digitalis Investigation Group (DIG Trial) 6,800 patients with ischemic and non-ischemic cardiomyopathy Mild to moderate heart failure Randomized to placebo or digoxin Digoxin has no effect on mortality Digoxin was associated with decreased risk of hospitalization (28% CHF, 6% all cause) Digoxin level investigation (post-hoc of DIG Trial) SDCs of 1.2 ng/mL and higher may be harmful SDCs of ~ 1.0 ng/mL may not provide any clinical benefit vs. placebo SDC of 0.5 to 0.8 ng/mL likely the optimal therapeutic range The Digitalis Investigation Group. N Engl J Med 1997;336:525-33. DIG Clinical Trial 50 Percent Mortality 40 Placebo N=3403 30 20 P=0.8 Digoxin N=3397 10 n = 6800 NYHA II-III 0 0 12 24 Months The Digitalis Investigation Group. N Engl J Med 1997;336:525-33. 36 48 Digoxin Concerns in the Elderly Narrow therapeutic index Age related decrease in renal function Results in increased serum digoxin concentrations May cause delirium Drug-drug interactions Affect digoxin bioavailability or excretion Increase risk of digoxin toxicity Reduced skeletal mass Reduced volume of digoxin distribution Aronow WS. J Am Geriatr Soc 1997;45:1252-8. Digoxin and Women Women digoxin (%) Women Placebo (%) p Absolute diff. between sexes (%)* Death from any cause 33.1 28.9 0.078 5.8 Death from CV causes 27.8 24.1 0.098 4.3 Death from worsening HF 12.4 11.9 0.750 2.8 Hospitalization for worsening HF 30.2 34.4 0.079 4.7 Outcome *Absolute difference between the effect of digoxin compared with the effect of placebo among women vs the same comparative effect in men; p was significant for death from any cause (p=0.034) and marginally significant for hospitalization for worsening HF (p=0.053). Rathore SS et al. N Engl J Med 2002;347:1403-11. Aldosterone Antagonists (AAs) (e.g., spironolactone, eplerenone) Block aldosterone-induced increases in vasoconstriction and sodium reabsorption “Addition of an aldosterone antagonist is reasonable in selected patients with moderately severe to severe symptoms of HF and reduced LVEF who can be carefully monitored for preserved renal function and normal potassium concentration.” SCr should be 2.5 mg/dL for men and 2.0 mg/dL in women K+ should be 5.0 mEq/L Eplerenone is NOT suggested for those over 75 years of age due to lack of survival benefit Monitor BMP and kidney function routinely Minimize concomitant use of potassium supplements, especially in combination with an ACEI or ARB Monitor for endocrine disturbances (e.g., gynecomastia) 2013 ACCF/AHA guidelines http://content.onlinejacc/org 71 Aldosterone Antagonists: Mechanism of Action Spironolactone ALDOSTERONE Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) • Retention Na+ • Retention H2O • Excretion K+ • Excretion Mg2+ Edema Collagen deposition Fibrosis Arrhythmias - myocardium - vessels Spironolactone: Indications Recent or current symptoms despite ACEI, diuretics, digoxin, and beta-blockers Recommended in advanced heart failure (II-IV), LVEF of ≤ 35%, in addition to ACEI and diuretics Hypokalemia -ESC HF guidelines 2001 2013 ACCF/AHA guidelines http://content.onlinejacc/org Background – The RALES Study Pts with NYHA Class III & IV HF on ACEI’s and loop diuretics were randomized to either 25 mg of spironolactone or placebo (avg dose = 26 mg) Spironolactone group had a 30% reduction in risk of death and 35% reduction in hospitalization for worsening HF Pitt B, et al. N Engl J Med 1999;341:709-17. RALES Trial: Spironolactone Annual Mortality Aldactone 18%; Placebo 23% 1.0 Survival 0.9 0.8 Aldactone 0.7 p < 0.0001 0.6 N = 1663 NYHA III-IV Mean follow-up 2 y 0.5 Placebo 0 RALES. N Engl J Med 1999;341:709 6 12 18 months 24 30 36 RALES Results – patients with HF Before RALES Before RALES After RALES Early 1994 Early 1999 Late 2001 (per 1000) (per 1000) (per 1000) Spiro Rx’s 34 30 149* Hyper K+ adms 2.4 4.0 11* Hyper K+ deaths 0.3 0.7 2.0* (*p<0.001) Spironolactone: Contraindications/ Risk-Benefit Considerations Contraindications Potassium concentration > 5.5 mEq/L Risk-benefit considerations Concomitant use with potassium supplements Life threatening hyperkalemia when used with ACE inhibitors or ARBs Eplerenone Potassium-sparing diuretic Lower affinity than spironolactone for progesterone and androgen receptors Ephesus trial showed statistically significant reduction in death versus placebo More expensive than spironolactone Those over 75 years did not respond to treatment Pitt B et al. N Engl J Med 2003; 348:1309-21. Pitt B 2003. Circulation 2003;108:1790 Hydralazine/Isosorbide Dinitrate Hydralazine is a peripheral arterial vasodilator Isosorbide is a peripheral venous vasodilator Working together they mimic vasodilating action of ACEIs “recommended to improve outcomes for patients self-described as African-Americans, with moderate-severe symptoms on optimal therapy with ACE inhibitors, beta blockers, and diuretics.” “patients with reduced LVEF who cannot be given an ACE inhibitor or ARB because of drug intolerance, hypotension, or renal insufficiency.” Monitor closely for hypotension, worsening edema, or headaches 2013 ACCF/AHA guidelines http://content.onlinejacc/org 79 Inotropic Support [e.g., Dopamine, Dobutamine, Milrinone (Primacor®) Increase force of cardiac contraction May provide symptom improvement but result in overall increase in mortality Central line access required Monitor for: Hypotension Arrhythmias Dizziness/Headache Adequate fluid intake Peripheral blood perfusion 2013 ACCF/AHA guidelines http://content.onlinejacc/org 80 2013 Guidelines for Inotropic Support Until definitive therapy (e.g. coronary revascularization, mechanical circulatory support (MCS), heart transplantation) or resolution of the acute precipitating problems. Patients with cardiogenic shock should receive temporary intravenous inotropic support to maintain systemic perfusion and preserve end-organ performance Continuous inotropic support reasonable as “bridge therapy” in patients with Stage D refractory to medication therapy and device therapy who are eligible for and awaiting MCS or cardiac transplantation Palliative therapy in stage D despite optimal medication therapy and device therapy who are not eligible for MCS or transplantation Potentially Harmful – absence of specific indications noted above 2013 ACCF/AHA guidelines http://content.onlinejacc/org 81 Therapeutic Concerns When Treating HF 82 Therapeutic Concerns with HF in the Elderly Problem Suggestions Hypotension Start therapies at lower doses and titrate upward slowly as tolerated Hyperkalemia (with ACEIs, ARBs, AAs) Avoid concomitant potassium supplements when possible Adjust diuretic use Monitor BMP routinely Other electrolyte abnormalities (e.g., hypokalemia) Monitor BMP routinely Monitor fluid status closely Adjust dietary intake as necessary 83 © Omnicare, Inc. 2013 Therapeutic Concerns with HF in the Elderly Problem Suggestions Digoxin toxicity Monitor closely for signs and symptoms (e.g., nausea, visual disturbances) Maintain serum drug concentration at 0.5-0.8 ng/mL Monitor kidney function and electrolytes Bradycardia Avoid other drugs that affect heart fate Titrate beta blocker dose slowly Gradually get out of bed/chair Monitor pulse routinely © Omnicare, Inc. 2013 84 Actions for Monitoring Heart Failure Routine assessment of vital signs (BP, pulse) Frequent assessment of weight (e.g., 3 times per week) Establish “dry weight” Establish threshold for notifying the prescriber (e.g., increase of 3 lbs) Monitor for signs of congestion and/or edema Increased cough or shortness of breath (especially at night or while lying down) Abdominal or lower extremity swelling Monitor for decreased blood perfusion Cool extremities Resting tachycardia Increased confusion BUN:Cr ratio 20:1 or greater (dehydration) © Omnicare, Inc. 2013 85 Heart Failure Clinics Dedicated clinics to heart failure Nurse practitioner trained in heart failure Greater access to a clinician “Brittle” patients need periodic medication adjustments Cheaper Reduces repeat hospitalizations Reduces morbidity and mortality 87 Ouslander JG, et al. INTERACT® Licensed Materials. http://www.interact2.net/index.aspx Back to the Case 88 83 year old Caucasian male, Clcr 63 mL/min, dry weight of 160 lb (72.2 kg) who presented to the nurse practitioner with complaints of shortness of breath and productive coughing for the last 4 weeks BP-90/64, HR-100, RR-20, T98.6 PMH: NYHA stage IV HF, glaucoma, coronary artery disease, hypertension, ocular strokes HPI: hospitalized the previous year twice for syncope associated with heart failure. Cardiac arrest during one hospitalization following administration of ramipril 2.5 mg CXR: no infiltrates Labs: WBC – wnl Medication aspirin EC clopidogrel furosemide metoprolol mirtazapine zolpidem simvastatin spironolactone digoxin Vitamin D3 Vitamin E latanoprost furosemide Dose 81 mg 75 mg 40 mg 50 mg 30 mg 5 mg 40 mg 25 mg 0.0625 mg 1,000 units (2 tabs) 400 units 1 drop each eye 40 mg 40 mg 40 mg (2 tabs) 40 mg (2 tabs) 40 mg (4 tabs) Frequency once daily once daily once daily twice daily at bedtime at bedtime at bedtime once daily once daily once daily once daily at bedtime wt ≤ 162 = no dose wt 163 - 167, 1 tab wt 168, 2 tabs wt 169, 2 tabs twice daily wt 170, 2 tabs twice daily Response of BP and Weight to Furosemide Therapy Zarowitz, BJ, Heart failure management and the war between evidence-based guidelines and common sense. Geriatr Nurs 2013; 34: 230 – 2. 90 Summary HF is associated with a high rate of emergency department visits, rehospitalizations, and overall morbidity and mortality Vigilance in monitoring for signs and symptoms of HF is essential Evidence-based medications and non-pharmacological interventions are an important part of improving the care of HF patients Early intervention in exacerbations can reduce rehospitalizations © Omnicare, Inc. 2013 91 Questions Thank you for this opportunity!