Pharmacologic Considerations for Reducing Hospital Readmission in Geriatric Patients with Heart Failure Barbara J. Zarowitz, Pharm.D. Chief Clinical Officer,

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
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 Medication Dose Frequency aspirin EC 81 mg once daily clopidogrel 75 mg furosemide 40 mg metoprolol 50 mg twice daily mirtazapine 30 mg at bedtime zolpidem 5 mg simvastatin spironolactone 25 mg digoxin mg Vitamin D3 1,000 units (2 tabs) Vitamin E 400 units latanoprost 1 drop each eye wt ≤ 162 = no dose wt , 1 tab 40 mg (2 tabs) wt 168, 2 tabs wt 169, 2 tabs twice daily 40 mg (4 tabs) wt 170, 2 tabs twice daily BP-90/64, HR-100, RR-20, T-98.6 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

Heart Failure Pathophysiology
What is Heart Failure? So let’s begin by discussing what heart failure is thereby look at the impact heart failure has on the patient and us as healthcare professionals. 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 So what is heart failure? HF is the inability of the heart to pump blood to the body sufficient to meet the body’s demands. And this results from either structural or functional cardiac disorders such that there is an impaired ability of the ventricle of the heart to either fill or eject blood. © Omnicare, Inc. 2013 7

Pathophysiology of Heart Failure
Causal Factors Myocardial Damage Myocardial Failure Cardiac output LV end diastolic pressure SVR (afterload)  Blood Volume (preload) The pathophysiology of heart failure is similar, regardless of underlying cause. Loss of cardiac output results in activation, and ultimately, over-activation, of the sympathetic nervous system and the renin-angiotensin-aldosterone axes. These compensatory systems are physiologic attempts to overcome the loss of cardiac output, but their over-activation contributes to excess edema, increased preload and increased afterload that further reduce myocardial performance. Drug therapy for heart failure is designed to interrupt the over activation of these compensatory systems, thereby improving patients symptoms and decreasing mortality. Compensatory Responses RAA SNS ANF Vasopressin

Pumping and Filling Problems and Heart Failure
SYSTOLIC DYSFUNCTION DIASTOLIC DYSFUNCTION NORMAL Diastole (Filling) The ventricles fill normally with blood The enlarged ventricles fill with blood The stiff ventricles fill with less blood than normal To understand how HF presents, it is helpful to understand how the heart normally functions in comparison to how the heart functions in either systolic or diastolic heart failure. Normally, the heart stretches as it fills with blood (during diastole), then contracts to pump out the blood (during systole). Heart failure due to systolic dysfunction usually develops because the heart cannot contract normally. It may fill with blood, but it cannot pump out as much of the blood it contains because the muscle is weaker. As a result, the amount of blood is pumped to the body and to the lungs is reduced, and the heart, particularly the left ventricle, usually enlarges. Heart failure due to diastolic dysfunction develops because the heart’s walls stiffen and may thicken so that the heart cannot fill normally with blood. The epidemic of diastolic dysfunction is secondary to that of type 2 diabetes and obesity. Consequently, blood backs up in the left atrium and lung (pulmonary) blood vessels and causes congestion. Nonetheless, the heart may be able to pump out a normal percentage of the blood it receives. Because the heart contracts to enclose the amount of blood that it contains, there is never any empty space in its chambers. The different amounts of blood entering or leaving the chambers is indicated by the thickness of the arrows. Systole (Pumping) The ventricles pump out ~60% of the blood 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 © Omnicare, Inc. 2013 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 This slide represents many facts about heart failure that are discussed in the American Heart Associations 2012 statistical report. In 2008, 1 in every 9 death certificates in the U.S. mentioned the diagnosis of heart failure. And overall an estimated 6.6 million US adults have HF with the incidence of HF increasing with age. An important fact on this slide is that 75% of patients with heart failure had hypertension prior to their being diagnosed with heart failure, so as we will discuss again later in this presentation, controlling a patient’s blood pressure is very important. Overall HF is more common among African Americans and among men. It is also important to realize that heart failure is considered the 2nd most preventable cause of emergency department visits, accounting for 19% of all visits. This also means that there are a lot of discharges associated with heart failure. 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: © Omnicare, Inc. 2013 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 This slide represents many facts about heart failure that are discussed in the American Heart Associations 2012 statistical report. In 2008, 1 in every 9 death certificates in the U.S. mentioned the diagnosis of heart failure. And overall an estimated 6.6 million US adults have HF with the incidence of HF increasing with age. An important fact on this slide is that 75% of patients with heart failure had hypertension prior to their being diagnosed with heart failure, so as we will discuss again later in this presentation, controlling a patient’s blood pressure is very important. Overall HF is more common among African Americans and among men. It is also important to realize that heart failure is considered the 2nd most preventable cause of emergency department visits, accounting for 19% of all visits. This also means that there are a lot of discharges associated with heart failure. 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 The incidence of heart failure approaches 10 cases per 1000 population among persons older than 65 years of age. Persons older than 65 years account for 80% of all heart failure hospitalizations. It is in fact a disease of the elderly where the incidence doubles with each decade of life over the age of 75 years. Eighty-eight percent of newly diagnosed heart failure cases occur in patients older than 65 years and 49% are older than 80 years American Heart Association. Heart disease and stroke statistics – 2004 Update. Dallas, Tex.: American Heart Association;2004. Senni M, Tribouilloy CM, Rodeheffer RJ et al. Congestive heart failure in the community. Circulation 1998;98:

Coronary artery disease
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 LVEF Reduced Normal Comorbidities Few Multiple RCTs Many Therapy Evidence-based Empiric Physician Cardiologist Primary care M=male; F=female; LVEF=left ventricular ejection fraction; RCT=randomized clinical trial The incidence and prevalence of heart failure (HF) increases progressively with age, and HF is currently the leading indication for hospitalization among older adults, as well as the most costly cardiovascular disorder in the Medicare population. In the United States, the prevalence of HF increases from <1% in adults under 50 years of age to >10% in persons over age 80. As HF has emerged as a major public health concern during the past 20 years, HF research has intensified. Indeed, there have now been hundreds of clinical trials evaluating the safety and efficacy of a broad range of pharmacologic therapies for the treatment of HF, and the results of these trials have led to the development of authoritative, evidence-based guidelines for HF management. Unfortunately, most of these studies have focused primarily on middle-aged HF patients, who may differ in many important respects from older HF patients. As a result, the generalizability of HF trials to older HF patients has been questioned, and it has been estimated that a minority of older HF patients would have been suitable candidates for the HF trials, even if older age had not been an exclusion. Despite limited data from clinical trials, clinicians must still provide appropriate care for the large number of elderly HF patients. Adapted from Rich RW. Drug therapy for heart failure in the elderly. Am J Ger Cardiol 2003;12:

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 acid-dependent 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 mL/min/year Physiologic changes of the GI tract with aging include increased gastric pH, delayed gastric emptying, reduced GI blood flow and slowed intestinal transit.2 As a result of these changes, older persons can be expected to exhibit decreased bioavailability of medications with acid-dependent absorption, such as iron, and slowed absorption of medications, especially those that are enteric coated.2 As an example, morphine clearance is reduced about 33% in older persons leading to longer half-lives and the need for lower oral doses. Similarly, the average clearance of propranolol declines whereas the oral bioavailability increases. In the elderly there is a doubling of the bioavailability of chlormethiazole, lidocaine, labetalol, verapamil, propranolol, and levodopa.3 The practical consequences of alterations in drug absorption, bioavailability and first-pass metabolism result in the need to start with lower doses and perhaps longer dosing intervals between doses to avoid the risk of drug accumulation and toxicity. Activity of the cytochrome (CYP) P450 isoenzymes, 1A2, 2C9, 2C19, 2E1, and 3A4, may be decreased but do not universally result in reduced clearance of substrates for those enzymes. Renal function progressively declines with age independent of the development of any renal disease. By age 85 the average creatinine clearance (Clcr) has declined to 50% of what it was at 25 years of age.2 The Baltimore Longitudinal Study of Aging prospectively found a decrease in Clcr of 0.75 mL/min/year.4 Most important, is the potential to under recognize the decline in renal function when evaluating serum creatinine, soley.5 Due to decreased production of creatinine with decreasing mobility and lower muscle mass in frail elderly individuals, serum creatinine can appear normal despite significant reductions in glomerular filtration rate (GFR) or Clcr.6-8 As a result, renal function should be estimated using either the Modification in Diet for Renal Disease (MDRD) or Cockcroft and Gault equations for GFR or Clcr, respectively. Most clinical laboratories calculate GFR by MDRD whenever a serum creatinine is analyzed. Clinical pharmacists routinely use the Cockcroft and Gault equation to estimate Clcr for dosing of renally-eliminated medications.

Underlying Causes of Heart Failure
Coronary Artery Disease Cardiovascular disease Valvular Heart Disease Infections Alcohol Heart Failure Hypertension Drugs This slide depicts a lot of the underlying causes of HF and once again it is important to note that a history of hypertension is listed. Note that valvular heart disease either prevents outflow from the ventricle, causing increased resistance (idiopathic hypertrophic subaortic stenosis) or incompetent valve causes ventricle to have hypertrophy to push out more blood as a percent will regurgitate back into the ventricle, i.e., valvular abnormality first, then ventricular changes. Alcohol: myopathy and dilation of ventricle i.e., primary toxicity to myocytes and dilation of ventricle. Shamsham F, Mitchell J. Essentials of the diagnosis of heart failure. AFP March Available at: Accessed Radiation 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 Valve disease Diabetes AFib Smoking Obesity/Diet Physical inactivity Alcohol consumption Mental stress Depression There are numerous risk factors for HF. While many of the risks are considered nonmodifiable, others can be managed or changed by a variety of lifestyle interventions and therapeutic treatments. As I mentioned earlier, hypertension is a well-established risk factor for HF and confers a two- to three-fold increased risk and treatment of hypertension has been associated with a reduction in that risk. All residents should be encouraged to adopt a lifestyle that reduces cardiovascular risk including smoking cessation, healthy diet, physical activity, and no (or low) alcohol consumption. Modifiable © Omnicare, Inc. 2013 Kenchaiah S et al. Med Clin N Amer 2004:88; 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 Prospective epidemiologic studies have identified several risk factors for heart failure. While there is no conclusive evidence that members of a particular ethnicity are at a greater risk of developing HF, the relative contribution of risk factors to HF may vary with ethnicity (e.g., more African Americans than Caucasians may have hypertension). Kenchaiah S et al. Med Clin N Amer 2004:88;

Medications That May Exacerbate Heart Failure
Agents Rationale Antiarrhythmic agents (avoid disopyramide and flecanide; amiodarone and dofetilide are acceptable, if necessary, for arrhythmia) Calcium channel antagonists (diltiazem, verapamil) Itraconazole Terbinafine Negative inotropic effects Alcohol (excessive amounts in predisposed patients) Doxorubicin Daunomycin Cyclophosphamide Cardiotoxic Androgens COX-2 inhibitors Estrogens Glucocorticoids Nonsteroidal anti-inflammatory drugs Salicylates (high doses) Sodium-containing drugs (e.g., ticarcillin) Thiazolidinediones (rosiglitazone, pioglitazone) Sodium and water retention Albumin Blood products Osmotic agents A number of medications, through the noted mechanisms, can exacerbate heart failure. Johnson JA, Parker RB, Patterson JH. Heart failure. In: DiPiro JT, Talbert RL, Yee GC et al, eds. Pharmacotherapy: a pathophysiologic approach. 5th edition. New York: McGraw-Hill;2002.pp

Signs and Symptoms of Heart Failure
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 Patients with heart failure present with a variety of symptoms, most of which are non-specific. The common symptoms of congestive heart failure include fatigue, edema, dyspnea, swollen ankles, and exercise intolerance, or symptoms that relate to the underlying cause. It is important to note that recognition of heart failure may be complicated in the nursing facility resident because of common comorbidities such as chronic obstructive pulmonary disorder (COPD), other lung conditions, and venous insufficiency. Staff should be trained to recognize and report a resident’s decreased activity level, shortness of breath, unexplained cough, unexpected weight gain, or new or increasing lower-extremity swelling. Urine production is changed and either increased or more commonly decreased. As the pump efficiency decreases, the kidney’s ability to filter also decreases, thus lowering urine output. Fluid is retained and backs up in the tissues. This is also one mechanism to loss of appetite because heart failure causes a congestive gastropathy, swelling the intestines with fluid and reducing appetite. © Omnicare, Inc. 2013

Congestive Heart Failure
Large left ventricle Thickening of the interlobular septa – Kerley B lines Peribronchial cuffing – wall is normally hairline thin Thickening of the fissures – fluid in the subpleural space in continuity with interlobular septa Pleural effusions

The FACES of Heart Failure
Fatigue Activities limited Chest congestion Edema or ankle swelling Shortness of breath A simpler way of describing the signs and symptoms of HF comes from The Heart Failure Society of America who for several years now have used the mnemonic “FACES”. F-fatigue A-activities limited C-chest congestion E-edema or ankle swelling S-shortness of breath HFSA. Who is the patient with heart failure? Available at: © Omnicare, Inc. 2013 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 B-type natriuretic peptide is a neurohormone secreted from the cardiac ventricles in response to ventricular stretch and pressure overload. BNP is cleared renally, so it may occasionally be falsely elevated in a patient with chronic kidney disease, but this test is most useful as corroborative evidence when the cause of shortness of breath is unclear. Elevated plasma BNP levels have been associated with reduced LVEF, LVH, elevated LV filling pressures, and acute MI and ischemia, although they can occur in other settings, such as pulmonary embolism and COPD. They are sensitive to other biological factors, such as age, sex, weight, and renal function. Levels of BNP may be meaningfully elevated in women and in people over 60 years of age who do not have HF, and thus BNP levels should be interpreted cautiously insuch individuals when distinguishing between cardiac and noncardiac causes of dyspnea. Elevated BNP levels may lend weight to a suspected diagnosis of HF or trigger consideration of HF when the diagnosis is unknown but should not be used in isolation to confirm or exclude the presence of HF. BNP (pg/mL) Interpretation <100 Reliably rules out HF Possible HF (~75% of cases are HF) >400 Suggestive of HF © Omnicare, Inc. 2013

BNP Diagnostic Algorithm
Dyspnea Physical Examination, Chest XR, ECG, BNP Level BNP <100pg/ml BNP pg/ml BNP >400pg/ml Baseline LV Dysfunction, Underlying Cor Pulmonale, Or Acute Pulmonary Embolism BNP testing is mostly used in the hospital setting and while it is useful for assessing acute episodes it is not a clear marker for heart failure diagnosis. CHF Very Unlikely (2%) CHF Very Likely (95%) Yes No Possible Exacerbation of CHF (25%) CHF Likely (75%) Adapted from: Tabbibizar R, Maisel A. Curr Opin Cardiol. 2002;17:343.

BNP concentration for the degree of heart failure severity
BNP for Diagnosis BNP concentration for the degree of heart failure severity BNP Concentration (pg/ml) B-type natriuretic peptide is a protein secreted from the cardiac ventricles in response to pressure overload. One potential application of measurements of BNP in blood is distinguishing dyspnea due to CHF from other causes. In this study, B-type natriuretic peptide concentrations were measured in a convenience sample of 250 predominantly male (94%) patients presenting to urgent-care and emergency departments of an academic Veteran's Affairs hospital with dyspnea. Results indicated that B-type natriuretic peptide blood concentration measurement appears to be a sensitive and specific test to diagnose CHF in urgent-care settings. n = 27 n = 34 n = 36 Maisel A et al. J Am Coll Cardiol 2001;37(2)

Evidence-Based Treatment Guidelines
Yancy CW, et al ACCF/AHA Heart Failure Guidelines Jessup M, et al ACCF/AHA guidelines for the diagnosis and management of heart failure in adults. Circulation ;119:1977–2016.

Heart Failure with Reduced EF

Treatment Approaches for Heart Failure
Now let’s shift our focus to treatment approaches for Heart Failure. 27

Goals of Treatment Survival Exercise capacity Quality of life
Morbidity Progression of disease Symptoms The objectives of treatment of the patient with heart failure are many, but they may be summarized in two principles: decrease symptoms and prolong life. In daily practice, the first priority is symptom control and the best plan is to adjust to the individual patient’s particular circumstances over the course of therapy. Nevertheless, the rest of the listed objectives should not be forgotten, as medical therapy now has the potential for decreasing morbidity (hospital admissions, embolism, etc.), increasing exercise capacity, improving the quality of life, retarding progression, and prolonging life. Crouch MA. Contemporary management of heart failure. Consult Pharm 2002;17:(Supp. 1)1-15. © 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) Overall our approach to heart failure should begin with making sure we have the proper diagnosis and to also stage the patient’s heart failure, which we will talk about on the next slide. The treatment plan should be established based upon patient-specific and patient-centered goals. Also non-pharmacological and evidence-based pharmacological interventions should be used. And then ongoing monitoring is essential which may include monitoring the impact of the patient’s diet, detecting and reporting changes in symptoms, such as sudden weight gain, and monitoring vital signs and other laboratory values that may be impacted by the medications we use. 29 © Omnicare, Inc. 2013

ACC/AHA Heart Failure Stage
Classification of HF ACC/AHA Heart Failure Stage NYHA Functional Class A 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) D Refractory HF requiring specialized interventions IV Symptomatic at rest resulting in inability to carry on any physical activity without discomfort (severe HF) Patients with heart failure are sometimes classified according to the amount of activity that they are able to perform before the signs and symptoms of heart failure are exacerbated. While two classification systems exist and are shown on this slide, traditionally, the system of classification has been the New York Heart Failure Association Functional Classification (NYHA), which rates the severity of heart failure from Class I (asymptomatic) up to Class IV (severe heart failure). The higher the NYHA functional class, the higher the patient mortality. In addition, improvements in NYHA functional class may be seen as a beneficial response to drug therapy for heart failure. It should be noted that some elderly patients may not ambulate enough to use this classification system. And it is important to note that this system may be used to track efficacy of therapy as patients are not locked into any one category. © Omnicare, Inc. 2013

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 In addition to staging a patient’s heart failure and using non-pharmacological and pharmacological interventions to manage HF, we must also remember that a number of medications, through the noted mechanisms, can cause or exacerbate heart failure. Whenever possible these medications should be avoided altogether or used in the lowest necessary dose whenever possible. 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

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 There are several non-pharmacological treatments that should be encouraged. One idea involves targeting the modifiable risk factors we discussed earlier, such as by promoting smoking cessation or stress management. Many dietary changes can also beneficial including: decreasing sodium to no more than 2,000 mg per day, limiting caffeine, which is a stimulant and puts added stress on the heart, and also limiting alcohol intake as alcohol can decreases the heart's ability to contract. Moderate exercise can also help the heart get stronger. Most people find that exercise has many benefits including improving their symptoms, reducing stress, promoting weight loss, and boosting energy levels. © 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 Now let’s switch our attention to the evidence-based medications that we have available for use. This slide outlines the most common therapies and in the remainder of this presentation we will be briefly discussing each of them. But before beginning our overview, I would point out the important quote at the bottom of the slide from the 2009 ACCF/AHA guidelines which state that “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” 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 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 For a long time, ACE inhibitors have been an often overlooked standard of care for HF even though they are associated with a significant decrease in mortality. ACEI’s work by lowering blood pressure through blood vessel relaxation and reducing sodium and water retention. Patients using ACEI should be monitored for low blood pressure, a persistent dry cough (which occurs in about 20% of patients receiving them), the rare but serious adverse effect of angioedema and elevated potassium and/or serum creatinine. It is not unusual to see an initial increase in both potassium and serum creatinine, but generally there is a return to or near baseline after a couple of weeks. Jessup M, et al ACCF/AHA Guidelines. Circulation ;119:1977–2016. Yancy CW, et al ACCF/AHA Guidelines. 34 © Omnicare, Inc. 2013

A.C.E. Kininase II ACE-I: Mechanism of Action VASOCONSTRICTION
VASODILATATION ALDOSTERONE PROSTAGLANDINS VASOPRESSIN Kininogen tPA SYMPATHETIC Kallikrein Angiotensinogen RENIN BRADYKININ Angiotensin I ACE-inhibitors competitively block the converting enzyme that transforms angiotensin I into angiotensin II. The reduction in angiotensin II levels explains its arteriovenous vasodilatory actions, as angiotensin II is a potent vasoconstrictor that augments sympathetic tone in the arteriovenous system. Additionally, angiotensin causes vasopressin release and produces sodium and water retention, both through a direct renal effect and through the liberation of aldosterone. Since converting enzyme has a similar structure to kinase II that degrades bradykinin, ACE-inhibitors increase kinin levels that are potent vasodilators (E2 and F2) and increase release of fibrinolytic substances such as tPA. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult Available at: Accessed A.C.E. Inhibitor Kininase II ANGIOTENSIN II Inactive Fragments

ACE Inhibitors RISKS BENEFITS Hypotension Prolonged survival*
Renal dysfunction Hyperkalemia Cough Angioedema Neutropenia Prolonged survival* Clinical improvement More stable clinical course Fewer hospitalizations Slower disease progression As with any therapy, the risks and benefits need to be compared. It is important to know how to monitor and manage adverse effects from ACE-inhibitor therapy, since these serve as barriers to prescribers. Cough is frequently observed in patients with heart failure and may be due to pulmonary congestion, not ACE-inhibitor therapy. The risk for hyperkalemia is minimal, however potassium supplements and potassium-sparing diuretics should be withheld when starting an ACE-inhibitor and may be re-instituted if needed. Hypotension and renal dysfunction are related events and can properly be managed by recognition of risk factors for their occurrence. AMDA. Heart failure. Clinical Practice Guideline 2002. Adapted from: Bottorff HF presentation. Omnicare Original HMP. * Not an indication for all ACEIs

ACE Inhibitors: Indications and Doses
Agent 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 mg qd 40 mg qd lisinopril (Prinivil®, Zestril®) mg qd 20 – 40 mg bid quinapril (Accupril®) 10 mg bid 40 mg bid ramipril (Altace®) 1.25 – 2.5mg qd 10 mg qd trandolapril (Mavik®) 1 mg qd 4 mg qd This table gives a list of ACE inhibitors and their indications from the USPDI and ACC/AHA Heart Failure Guidelines. There are basically 3 classes of ACE inhibitors: 1) Captopril, in a class by itself, is an active compound. 2) the prodrugs, enalapril, fosinopril, quinapril, verapamil, and trandolapril, are all converted in the liver to active metabolites, and 3) lisinopril, also in a class by itself, is water soluable, not metabolized or excreted by the kidney. Despite the lipid solubility and tissue penetration of some of the active forms of the prodrugs, there is no firm evidence that they perform any better than lisinopril. The major site of ACE inhibition is in the vascular endothilium accessible to all ACE inhibitors. ACE = angiotensin-converting enzyme, LV = left ventricular HF = heart failure, MI = myocardial infarction

ACE Inhibitors, Heart Failure, and Mortality Reduction
STUDY ACE-I Patients Duration Results CONSENSUS Mean age 71 Enalapril mg/d vs. placebo N=253 Class IV HF 12 months 6 month mortality ↓ 40% 1 year mortality ↓ 31% Death from progressive HF ↓ 50% SOLVD Mean age 60 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% AIRE Mean age 65 Ramipril 2.5-5 mg bid N=2,006 HF post MI 30 months All cause mortality ↓ 17% Risk of 1st event ↓ 19% SAVE Captopril mg/d vs. placebo N=2,231 EF < 40% Post MI All cause mortality ↓ 19% CV death ↓ 21% CHF development ↓ 37% Recurrent MI ↓ 25% There are several large-scale trials that have evaluated the effects of ACE inhibitors in heart failure. They have all demonstrated reductions in mortality.

ATLAS Trial Low-dose vs. high dose lisinopril N = 3,164
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) Angiotensin-converting enzyme (ACE) inhibitors are generally prescribed by physicians in doses lower than the large doses that have been shown to reduce morbidity and mortality in patients with heart failure. It is unclear, however, if low doses and high doses of ACE inhibitors have similar benefits. The ATLAS trial showed that when compared with the low-dose group, patients in the high-dose lisinopril group had a significant 12% lower risk of death or hospitalization for any reason (P=0.002) and 24% fewer hospitalizations for heart failure (P=0.002). These findings indicate that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor (unless these are the only doses that can be tolerated) and suggest that the difference in efficacy between intermediate and high doses of an ACE inhibitor (if any) is likely to be very small. Packer M, Poole-Wilson PA, Armstrong PW et al. Comparative Effects of Low and High Doses of the Angiotensin-Converting Enzyme Inhibitor, Lisinopril, on Morbidity and Mortality in Chronic Heart Failure. Circulation 1999;100: Packer M et al. Circulation 1999;100:

CONSENSUS Trial Placebo Enalapril Probability of death Months 0.8 0.7
0.6 p< 0.001 0.5 Probability of death 0.4 p< 0.002 0.3 Enalapril CONSENSUS=Cooperative New Scandinavian Enalapril Survival Study. CONSENSUS. Prolonged administration of ACE-inhibitors reduces mortality in symptomatic heart failure. The first study to demonstrate this effect was CONSENSUS I. This graph shows the cumulative mortality curves of the treatment and placebo group in this randomized, double-blind trial. The study analyzed the effect of enalapril on prognosis of 253 patients with class IV heart failure, who also received digitalis, diuretics, and conventional vasodilators. At the end of 6 months of treatment, there was a clear-cut improvement in functional class, a reduction in the need for medications, and a 40% reduction in mortality (p<0.002). After 12 months the mortality reduction was 31% (p<0.001). Nonetheless, there were no differences in the incidence of sudden death between the two groups, or in the sub-group that received other conventional vasodilators. Another characteristic of this study was variability of the dose that was used for each patient (adjusted for tolerance and symptoms): mg/day. This aspect shows the importance of individualized treatment for heart failure patients. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study. N Engl J Med 1987;316: 0.2 0.1 1 2 3 4 5 6 7 8 9 10 11 12 Months CONSENSUS. N Engl J Med 1987;316:

SOLVD Trial (Treatment Arm)
0.8 Placebo Placebo n=1284 0.7 0.6 p< 0.001 0.5 p = p< 0.002 Enalapril n=1285 Percent Survival 0.4 Enalapril 0.3 SOLVD=Studies of Left Ventricular Dysfunction SOLVD study-symptomatic heart failure. Mortality curves in patients with clinical heart failure in the SOLVD treatment study. In this study, 2,589 symptomatic heart failure patients with EFs<35% (90% in functional class II – III) were randomized to receive enalapril or placebo. Mortality reduction over a 41 month follow-up period was 39.7% in the enalapril arm and 35.2% in the placebo arm (p<0.004). The mortality reduction was chiefly mediated through less progression of heart failure; deaths due to arrhythmia were not reduced. Additionally, the enalapril group required fewer hospitalizations for heart failure. It is important to note that the mortality rate for symptomatic patients in this trial is frightening at 12 months. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991;325: 0.2 n = 2589 CHF - NYHA II-III - EF < 35 0.1 6 12 18 24 30 36 42 Months SOLVD. N Engl J Med 1991;325:

ACE Inhibitors: Contraindications/ Risk-Benefit Considerations
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 There are few absolute contraindications for the use of ACE-inhibitors. The most important one is the presence of renal artery stenosis. The most frequent contraindication is intolerance of the drug. Hypotension, the presence of renal insufficiency, or hyperkalemia limits their use, or the ability to administer adequate doses, in up to 20% of patients. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult Available at: Accessed

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: Hypotension Angioedema (<1%) Elevated potassium Elevated serum creatinine The next class, the angiotensin receptor blockers are similar in benefit to ACEI and are often used when a patient cannot tolerate an ACEI such as for the persistent non-productive cough. And once again the monitoring for the ARBs is very similar. Addition of an ARB may be considered in persistently symptomatic patients with reduced EF who are already being treated with an ACEI and a beta blocker in whom an aldosterone antagonist is not indicated or tolerated ACCF/AHA Guidelines Yancy CW, et al ACCF/AHA Heart Failure Guidelines Jessup M, et al ACCF/AHA guidelines Circulation ;119:1977–2016. 43 © Omnicare, Inc. 2013

Angiotensin I ANGIOTENSIN II
Angiotensin II Receptor Blockers (ARB): Mechanism of Action RENIN Angiotensinogen Angiotensin I ANGIOTENSIN II ACE Other pathways AT1 Receptor Blockers RECEPTORS Angiotensin II has different effects mediated via specific receptors. There are two types of tissue receptors for angiotensin: AT1 and AT2. Stimulation of AT1 receptors has a proliferative and vasoconstrictor effect, while stimulation of AT2 receptors has the opposite effects, that is, vasodilatory and antiproliferative. In the treatment of heart failure, specific blockade of the AT1 receptors is desirable. Drugs which create a selective and competitive block of the AT1 receptors include: losartan, valsartan, irbersartan, and candesartan. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult Available at: Accessed AT1 AT2 Vasoconstriction Proliferative Action 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.

Val-HeFT: Comparison of Event Rates
Valsartan (%) Placebo RR* p 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 When compared to placebo, there was a statistically significant reduction in all cause mortality (p=0.017) and rate of hospital admissions (p<0.001) with valsartan. Maggioni AP, Anand I, Gottlieb SO, Latini R, Tognoni G, Cohn JN; Val-HeFT Investigators (Valsartan Heart Failure Trial). Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol. 2002;40: Maggioni AP et al. J Am Coll Cardiol 2002;40:

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 The CHARM Program, one of the largest trials ever undertaken in heart failure patients, consisted of three simultaneous, parallel arms in which three different populations were studied prospectively with the same doses of candesartan or placebo. The three arms of the study were: • CHARM-Alternative: Patients with a left ventricular ejection fraction of 40% or less who could not tolerate an ACE inhibitor • CHARM-Added: Patients with a left ventricular ejection fraction of 40% or less who were currently taking an ACE inhibitor, with or without a beta-blocker • CHARM-Preserved: Patients with a left ventricular ejection fraction greater than 40%. CHARM was the only clinical trial of ARBs to date to show a consistent benefit in terms of lower morbidity and mortality rates in patients with heart failure and decreased left ventricular systolic function. The findings also place candesartan among the ranks of ACE inhibitors, beta blockers, and spironolactone—drugs shown previously to alter the natural history of heart failure progression and to decrease mortality in patients with heart failure and left ventricular systolic dysfunction. McMurray JJV, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003; 362:767–71. Granger CB, McMurray JJV, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet, 2003;362:772–6. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003; 362:777–81.

Combination of ACEI and ARB in Heart Failure Management
Relative Risk of Death Background Therapy N ACEI +, Beta Blocker ACEI +, Beta Blocker ACEI -, Beta Blocker ACEI -, Beta Blocker In the Valsartan heart failure trial (Val-HeFT), about 35% of the treatment and placebo arms were also taking a beta-blocker. More than 90% of patients in both arms were taking an ACEI. As noted in the above analysis of subgroups, the risk of death was increased significantly (by about 40%) in those receiving ARB + ACEI + Beta-blocker. Cohn JN, Tognoni G. A randomized trial of the angiotensin receptor blocker valsartan in chronic heart failure. NEJM 2001;345: 1.0 Valsartan Better Placebo Better P=0.009 Test for heterogeneity Cohn JN et al. NEJM 2001;345:

All-Cause Mortality in the VALIANT Study
Group All-cause mortality (%) Hazard ratio (95% CI) compared with captopril p value Captopril (n=4909) 19.5 - Valsartan (n=4909) 19.9 1 ( ) 0.98 Combination (n=4885) 19.3 ( ) 0.73 VALIANT = valsartan in Acute Myocardial Infarction This was a double-blind trial comparing the effect of the angiotensin-receptor blocker valsartan, the ACE inhibitor captopril, and the combination of the two on mortality in a population of patients. The primary end point was death from any cause. The investigators found no difference in all cause mortality between the groups. They concluded that valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after myocardial infarction. Combining valsartan with captopril increased the rate of adverse events without improving survival. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349: Pfeffer MA et al. N Engl J Med 2003; 349:

VALIANT: Cardiovascular Death, Recurrent MI, or Heart Failure Hospitalization
Secondary End Point Group 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 ( ) 0.20* Combination (n=4885) 0.97 ( ) 0.37* The secondary end point in the VALIANT trial was cardiovascular death, recurrent myocardial infarction or hospitalization for heart failure. As with the primary endpoint, the investigators found no difference between captopril, valsartan or the combination. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349: *Not significant Pfeffer MA et al. N Engl J Med 2003; 349:

VALIANT: Incidence of Adverse Events
Group 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* The valsartan + captopril group (combination) had the most drug-related adverse events; 9% of the combination group discontinue therapy. Hypotension (18.2%), renal causes (4.8%), and cough (4.6%) were the most common ADEs resulting in a dose reduction. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349: * Significant difference from captopril (p<0.05) Pfeffer MA et al. N Engl J Med 2003; 349:

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 pre-treatment 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 The next class commonly used are the beta blockers and specifically three are approved for use in HF – bisoprolol, carvedilol and the extended release metoprolol succinate. Beta blockers are believed to prevent the already damaged heart from speeding up. And while they are recommended, they should only be started in patients with stable fluid volume and because they may initially worsen HF the diuretic dose may need adjusted. Patients receiving beta blockers must have both their pulse and blood pressure routinely monitored. Also, for diabetic patients, it is important to recognize that other than sweating, the typical symptoms of hypoglycemia may be masked by use of a beta blocker. 2013 ACCF/AHA guidelines.

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, then increase to 5.0 mg/day in 2-4, weeks, then increase to maximum 10 mg/day Carvedilol (Coreg®) 3.125 mg twice daily Increase to 6.25 mg bid in 2-4 weeks, then increase to 12.5 mg bid in 2-4 weeks, then increase to maximum 25 mg twice daily (50 mg twice daily if > 85 kg) Metoprolol extended release (Toprol XL®) 12.5 mg/day 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 A key goal should be to titrate beta-blockers to the maximum tolerated dose. In most clinical trials, the dose was doubled every 2-4 weeks until the target dose was reached. In patients will low systolic blood pressure (< 90 mmHg) or a low pulse rate (< 60 beats/min) or recent changes in fluid status, the titration rate may need to be decreased (e.g. longer interval between increases). Some patients will not reach the target dose, so they should be maintained on the maximum tolerated dose. The risk for symptomatic hypotension is greatest within hours of a dosage increase, so the patient and staff should be educated about this risk. Sometimes, hypotension can be managed by dosing beta-blockers, ACE/ARBs, and diuretics at different times of the day. Temporary dose reductions of ACE/ARB should be considered if necessary to increase tolerance of beta-blockers during titration. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult Available at: Accessed Farrell MH, Foody JM, Krumholz HM. B-blockers in heart failure. Clinical applications. JAMA 2002;287: *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:

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 Both loop and thiazide diuretics are commonly used in HF and these drugs works by reducing fluid volume thereby decreasing the workload on the heart. Generally loop diuretics like furosemide are more effective than thiazides, but in patients with diuretic resistance combination with both types may become necessary. It is very important that HF patients on diuretics be closely monitored for changes in weight and also have their potassium monitored as supplementation is often necessary. 2013 ACCF/AHA guidelines . 54

Inhibit reabsorption of Na in distal convoluted and collecting tubule
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 Diuretics Inhibit exchange of Cl-Na-K in thick segment of the ascending loop of Henle Diuretics interfere with the sodium retention of HF by inhibiting the reabsorption of sodium or chloride at specific sites in the renal tubules. Loop diuretics (e.g., furosemide, torsemide) act at the loop of Henle whereas thiazides (e.g., metolazone) and potassium-sparing diuretics (e.g., spironolactone) act in the distal portion of the tubule. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult Available at: Accessed Loop of Henle Collecting Tubule

Loop Diuretics Mechanism of action Adverse reactions
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) Drugs acting on the ascending limb of the loop of Henle in the kidney are called loop diuretics and are considered the agents of choice for the treatment of heart failure. In addition to electrolyte abnormalities and contraction alkalosis, loop diuretics have other adverse effects. Skin reactions, from photosensitivity to rashes are not uncommon, as well as hypotension and orthostasis. Diuretics also cause vasodilation increasing capacitance and effectively relieving the heart of its fluid burden while the fluid remains in the body. It shifts the vascular compartment the fluid is in (venous versus arterial or lungs) and helps shift the congestion away from the lungs even before the diuretic effect. This is why loop diuretics are such effective rescue agents because they divert fluid away from the lungs even before the patient urinates out the fluid. It is important to note that diuretics must achieve a certain serum concentration for the effects to be achieved. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult Available at: Accessed Kubo SH et al. Am J Cardiol 1987;60:1322 MRFIT. JAMA 1982;248:1465

Thiazide Diuretics Mechanism of action Adverse reactions
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) Thiazide diuretics inhibit sodium reabsorption in the distal renal tubule and generally produce more potassium wasting than with loop diuretics. Thiazide diuretics share most of the side effects seen with loop diuretics. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult Available at: Accessed Sharpe N. Heart failure. Martin Dunitz 2000;43 Kubo SH , et al. Am J Cardiol 1987;60:1322 MRFIT, JAMA 1982;248:1465 Pool Wilson. Heart failure. Churchill Livinston 1997;635

Torsemide Loop diuretic Consistent absorption Reduced fatigue
Fewer hospitalizations Lower cost of care Compared with furosemide-treated patients, torsemide-treated patients were less likely to be readmitted for heart failure and for all cardiovascular causes, and were less fatigued. If our results are confirmed by blinded trials, torsemide may be the preferred loop diuretic for patients with chronic heart failure. 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: 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:

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 In the treatment of more advanced stages of heart failure, diuretics may fail to control salt and water retention despite the use of appropriate doses. Diuretic resistance may be caused by decreased renal function and reduced and delayed peak concentrations of loop diuretics in the tubular fluid, but it can also be observed in the absence of these pharmacokinetic abnormalities. When the effect of a short acting diuretic has worn off, postdiuretic salt retention will occur during the rest of the day. Chronic treatment with a loop diuretic results in compensatory hypertrophy of epithelial cells downstream from the thick ascending limb and consequently its diuretic effect will be blunted. De Bruyne LKM. Mechanisms and management of diuretic resistance in congestive heart failure. Postgraduate Medical Journal. 2003;79:

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 The vast majority of patients presenting with acute symptoms of fluid overload are responsive to diuretic drugs, at least initially. However, after chronic exposure to loop diuretics, some patients will require increasing doses and eventually develop diuretic resistance. After excluding compliance problems, higher doses and more frequent administration should be tried. Switching to the intravenous route bypasses the gastrointestinal tract and can overcome problems associated with delayed absorption. Continuous intravenous infusion has been shown to be more efficient than intermittent bolus administration. The addition of a thiazide diuretic to treatment with loop diuretics will usually establish a diuresis even in patients not responsive to other diuretic regimens. The mechanism behind this synergistic effect is hypertrophy of cells in the distal collecting tubule (with resulting increases in salt transport capacity) that occurs after chronic high dose loop diuretic therapy. When diuretic resistance has been treated successfully, heart failure treatment should be optimized according to the most recent guidelines in order to reduce mortality. Traditionally metolazone has been used in combination with loop diuretics, although there is no theoretical advantage of one thiazide over another. De Bruyne LKM. Mechanisms and management of diuretic resistance in congestive heart failure. Postgraduate Medical Journal. 2003;79:

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 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 ng/mL is the recommended therapeutic range Although it is on the updated 2012 Beers’ Criteria for doses higher than mg, digoxin is useful in increasing the force and velocity of the heart’s ability to contract while also reducing the overall heart rate. Patients on digoxin must have their pulse monitored prior to each dose and they need to be closely monitored for signs of digoxin toxicity. Classic symptoms of digoxin toxicity include nausea, decrease appetite, visual disturbances such as seeing green or yellow halos, confusion, weakness, and dizziness. Patients on digoxin should have their serum electrolytes and a digoxin concentration routinely monitored. 2013 ACCF/AHA guidelines.

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 Digitalis glycosides (e.g., digoxin) inhibit sodium-potassium adenosine triphosphatase which results in an increase in the contractile state of the heart. The benefits seen with this drug treatment on heart failure are related to enzyme inhibition in noncardiac tissue. Brewer GM. Pharmacology. W.B. Saunders. Philadelphia, PA

Digoxin: Mechanism of Action
- Na-Ca Exchange Na-K ATPase Na+ K+ Na+ Ca++ Digoxin attaches to specific receptors which form a part of the enzyme, Na+/K+-dependent ATP-ase (sodium pump), inhibiting it. This blockade produces a progressive increase in the intracellular concentration of Na, which in turn activates the exchange of Na+-Ca++ and increases the influx of Ca++ and its intracellular concentration, [Ca++]i. This increase in the [Ca++]i at the level of the contractile proteins explains the resultant increase in cardiac contractility. The benefits of digoxin may also be related to enzyme inhibition in noncardiac tissues including vagal nerves which sensitive cardiac baroreceptors resulting in decreased sympathetic outflow from the CNS. In additon, inhibition of Na-K-ATPase in the kidney by digoxin may decrease renal tubular reabsorption of sodium resulting in suppression of renin secretion from the kidneys. These actions collectively suggest that digoxin acts in heart failure principally by attenuating the activation of the neurohormonal system rather than by a positive inotropic action. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult Available at: Accessed Myofilaments Ca++ K+ Na+ CONTRACTILITY

Digoxin: Clinical Use Therapy is initiated at dose of 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 Digitalis is initiated at a dose of mg/day in the elderly or those patients with impaired renal function. This medication should be used with caution in patients with significant sinus or atrioventricular block and it is 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 Jr, Gheorghiade M, Uretsky BF, Patterson JH, et al. Clinical benefits of low serum digoxin concentrations in heart failure. J Am Coll Cardiol 2002;39: Adams KF et al. J Am Coll Cardiol 2002;39:

Risk of Treatment Failure Based on Randomization SDC Group
Treatment Group Relative Risk 95% CI P Value Digoxin concentration (SDC) < 0.9 ng/ml 0.09 0.018 > ng/ml 0.22 0.004 > 1.2 ng/ml 0.17 <0.001 These investigators found that the lowest risk of treatment failure was in the low serum digoxin concentration group. Effectiveness at low doses is believed to be mediated by neuroendocrine mechanisms. Adams KF Jr, Gheorghiade M, Uretsky BF, Patterson JH, et al. Clinical benefits of low serum digoxin concentrations in heart failure. J Am Coll Cardiol 2002;39: 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:

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 results of the Digitalis Investigator Group-DIG study, which included 7,788 patients with heart failure in sinus rhythm, functional class II-III and LVEF < 45%. The patients were treated with digoxin or placebo, in addition to conventional therapy over a mean of 37 months ( months). No differences in mortality were observed between the two treatment groups. A post-hoc analysis of the DIG trial indicated that the effectiveness of digoxin in the DIG trial varied according to patients' SDCs, such that higher SDCs were associated with higher rates of mortality and hospitalization. Furthermore, our analyses suggest that previously accepted SDCs of 1.2 ng/mL and higher may be harmful and that currently recommended therapeutic SDCs of approximately 1.0 ng/mL may not provide any clinical benefit compared with placebo. Our findings suggest that an SDC of 0.5 to 0.8 ng/mL likely constitutes the optimal therapeutic range for digoxin therapy among men with stable heart failure and left ventricular dysfunction. The Digitalis Investigation Group. The effect of digoxin on morbidity and mortality in patients with heart failure. N Engl J Med 1997;336: Rathmore SS, Curtis JP, Wang Y et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003;289:871-8. The Digitalis Investigation Group. N Engl J Med 1997;336:

DIG Clinical Trial Percent Mortality Months 50 40 30 20 10 Placebo
Placebo N=3403 Percent Mortality P=0.8 The results of the Digitalis Investigator Group-DIG study, which included 7,788 patients with heart failure in sinus rhythm, functional class II-III and LVEF <45%. The patients were treated with digoxin or placebo, in addition to conventional therapy over a mean of 37 months ( months). No differences in mortality were observed between the two treatment groups. The Digitalis Investigation Group. The effect of digoxin on morbidity and mortality in patients with heart failure. N Engl J Med 1997;336: Digoxin N=3397 n = 6800 NYHA II-III 12 24 36 48 Months The Digitalis Investigation Group. N Engl J Med 1997;336:

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 Digoxin has a narrow therapeutic index, especially in older persons. Age-related decrease in renal function increases serum digoxin levels in older persons. The reduction in skeletal mass in older persons reduces the volume of distribution of digoxin, increasing serum digoxin levels. Older persons are also more likely to be taking drugs that interact with digoxin by interfering with its bioavailability or excretion. E.g., verapamil, spironolactone, triamterene, tetracycline, clarithromycin and erythromycin, amiodarone, and other drugs increase serum digoxin concentrations.Therefore older persons receiving these drugs are at increased risk for developing digitalis toxicity. Aronow WS. Treatment of congestive heart failure in older persons. J Am Geriatr Soc 1997;45: Aronow WS. J Am Geriatr Soc 1997;45:

Absolute diff. between sexes (%)*
Digoxin and Women Outcome 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 To tease out the all-cause mortality benefits of digoxin in men versus women, researchers conducted a post-hoc analysis of DIG (6800 patients). Although male digoxin recipients and male placebo recipients had similar all-cause mortality rates (35.2% and 36.9%, P=0.22), the rate among female digoxin recipients was somewhat higher than among female placebo recipients (33.1% vs. 28.9%, P=0.078). A significant interaction between sex and digoxin use was found (P=0.034), such that digoxin's effect on all-cause mortality was an absolute 5.8% higher in women than in men. In a multivariable analysis, digoxin was associated with a nonsignificantly lower all-cause mortality risk among men and a significantly higher risk among women. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002;347: *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:

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) Aldosterone Antagonists as the class name implies block some of the problems associated with aldosterone. However, because these drugs effect the excretion of potassium they should not be used in patients with underlying hyperkalemia and use of potassium supplements should be avoided or minimized especially in patients who are also receiving an ACEI or ARB. Although listed on this slide, eplerenone is not recommended for patients over the age of 75 as benefit has not been proven. 2013 ACCF/AHA guidelines

Aldosterone Antagonists: Mechanism of Action
Spironolactone ALDOSTERONE Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) Collagen deposition Fibrosis - myocardium - vessels Retention Na+ Retention H2O Excretion K+ Excretion Mg2+ Edema Aldosterone acts directly on specific receptors. At the renal level it produces retention of sodium and water, resulting in an increase in preload and afterload, edema formation and the appearance of symptoms of pulmonary and systemic venous congestion. In addition, it increases the elimination of potassium and magnesium, creating an electrolyte imbalance which may be responsible in part for cardiac arrhythmias. At the tissue level, aldosterone stimulates the production of collagen, being in large part responsible for the fibrosis that is found in hypertrophied myocardium and in the arterial walls of patients with heart failure. The beneficial effects of spironolactone derive from the direct and competitive blockade of specific aldosterone receptors. Aldosterone inhibitors therefore have three types of effects: - Diuretic effect, which is most noticeable when fluid retention and increased levels of aldosterone are present. - Antiarrhythmic effect, mediated by the correction of hypokalemia and hypomagnesemia. Antifibrotic effect. This effect, demonstrated in animal models, can contribute to a decrease in the progression of structural changes in patients with heart failure. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult Available at: Accessed Arrhythmias

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

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. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341: (RALES: Randomized Aldactone Evaluation Study.) Pitt B, et al. N Engl J Med 1999;341:

RALES Trial: Spironolactone
Annual Mortality Aldactone 18%; Placebo 23% 1.0 0.9 0.8 0.7 0.6 0.5 Survival Aldactone p < Aldosterone is important in the pathophysiology of heart failure. In a double-blind study, investigators enrolled 1,663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an ACEI, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes. The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46%) and 284 in the spironolactone group (35%; relative risk of death, 0.70; 95% CI, 0.60 to 0.82; P<0.001). This 30% reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35% lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95% CI, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in HF symptoms, as assessed on the basis of the NYHA functional class (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients. Pitt B, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341: (RALES: Randomized Aldactone Evaluation Study.) N = 1663 NYHA III-IV Mean follow-up 2 y Placebo 6 12 18 24 30 36 RALES. N Engl J Med 1999;341:709 months

RALES Results – patients with HF
Before RALES After RALES Early 1994 (per 1000) Early 1999 Late 2001 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) Publication of RALES was associated with an abrupt increase in the number of prescriptions for spironolactone for older patients who were receiving ACEIs. At the same time there was an increase in hospital admissions for hyperkalemia and in-hospital death. Juurlink DN et al. Rates of Hyperkalemia After Publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:

Spironolactone: Contraindications/ Risk-Benefit Considerations
Potassium concentration > 5.5 mEq/L Risk-benefit considerations Concomitant use with potassium supplements Life threatening hyperkalemia when used with ACE inhibitors or ARBs Caregivers should be aware of potential adverse reactions to aldosterone antagonists. The main contraindications of therapy include concomitant use with potassium supplements. Spironolactone has been demostrated (RALES) to significantly improve outcomes in patients with heart failure, and the use of ACE-inhibitors is also indicated in these patients, But life-threatening hyperkalemia can occur when these drugs are used together. AMDA. Heart failure. Clinical Practice Guideline 2002. Juurlink DN, Mamdani MM, Lee DS et al. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med 2004;351:

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. Pitt B Aldosterone Blockade in Patients With Systolic Left Ventricular Dysfunction. Circulation 2003;108:1790. Pitt B et al. N Engl J Med 2003; 348: Pitt B 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 This slide is about the use of combining hydralazine and isosorbide to also help produce vasodilation. This combination is recommended for patients with persistent symptoms despite the use of the other recommended therapies and in African-American patients with moderate to severe symptoms on optimal therapy, and also for patients who cannot tolerate an ACEI or ARB. Patients receiving this combination therapy should be closely monitored for low blood pressure, worsening edema, and headaches. 2013 ACCF/AHA guidelines 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 The final type of drug therapy I want to discuss are the inotropic therapies. These IV medications include dopamine, dobutamine, or milrinone and all work on increasing the force of cardiac contraction. Even though these drugs result in an overall increase in mortality, they are often utilized in palliation of severe end-stage HF symptoms. They do require having central line access and patients receiving these medications must not only maintain adequate fluid intake but must be monitored for low blood pressure, heart arrhythmias, dizziness, headaches, and inadequate blood perfusion. 2013 ACCF/AHA guidelines

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

Therapeutic Concerns When Treating HF
In the remaining slides, I want to review some of the more common therapeutic concerns when treating HF and then discuss some of the actions you as nurses can take to help protect your residents with 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 fluid status closely Adjust dietary intake as necessary On this first slide we see the problems of hypotension, hyperkalemia, and other electrolyte abnormalities. Because all of the medications used to treat HF can cause hypotension, doses for all of these medications should be started low and titrated up very slowly as tolerated. ACEIs, ARBs, and aldosterone antagonists are commonly associated with hyperkalemia so avoiding or minimizing use of potassium supplements is suggested. In the case of both hyperkalemia and other electrolyte abnormalities, routine monitoring of a BMP is suggested as well as adjusting the patient’s diuretic doses, fluid intake, and overall dietary intake. © Omnicare, Inc. 2013 83

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 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 Specific to digoxin, again I want to remind you that digoxin toxicity is a serious concern for elderly patients so in addition to monitoring for the classic symptoms of toxicity, it is important that patients routinely have their digoxin concentrations and kidney function monitored. With regard to bradycardia, we need to evaluate all of the medications a patient is receiving to see if those drugs may also be impacting a patient’s heart rate and we should be very careful when titrating the dose of beta blocker therapy. © 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) Finally, on this slide are the various action steps you can take to help closely monitor your residents with HF. Specifically, you should be routinely assessing the patient’s BP and pulse. Frequent monitoring for weight gain is imperative and this involves not only determining a dry weight but also determining how much of a weight gain should result in the prescriber being contacted. Monitoring should also include watching for signs of worsening congestion or edema and also decreased blood perfusion. © Omnicare, Inc. 2013

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 Dedicated heart failure clinics usually have a nurse practitioner trained in heart failure disease management. The greater access to a clinician who can help “brittle” heart failure patients to adjust their medications helps keep them from needing repeat hospitalizations. A result of which reduces costs, morbidity and mortality.

This slide contains a Care Path from the INTERACT Project by Dr
This slide contains a Care Path from the INTERACT Project by Dr. Joseph Ouslander. This Care Path can be utilized to help identify as well as respond to signs and symptoms of heart failure. This Care Path and many other tools from the INTERACT project have been made available to you on Omniview so I hope you will check them out. Ouslander JG, et al. INTERACT® Licensed Materials.

Back to the Case

83 year old Caucasian male, Clcr 63 mL/min, dry weight of 160 lb (72
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, T-98.6 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 Dose Frequency aspirin EC 81 mg once daily clopidogrel 75 mg furosemide 40 mg metoprolol 50 mg twice daily mirtazapine 30 mg at bedtime zolpidem 5 mg simvastatin spironolactone 25 mg digoxin mg Vitamin D3 1,000 units (2 tabs) Vitamin E 400 units latanoprost 1 drop each eye wt ≤ 162 = no dose wt , 1 tab 40 mg (2 tabs) wt 168, 2 tabs wt 169, 2 tabs twice daily 40 mg (4 tabs) wt 170, 2 tabs twice daily

Response of BP and Weight to Furosemide Therapy
The physician noted that he was not receiving an ACEI and attributed the coughing and edema to worsened HF rather than infection The metoprolol dose was increased to 1 ½ tabs twice daily, (75 mg twice daily), furosemide to 80 mg once daily, and enalapril 2.5 mg twice daily was added. Fortunately, the patient went to the Wellness Center and asked the nurse practitioner about his new pills indicating that he had had a “bad spell” when he was given one medicine in the hospital. The nurse practitioner called the hospital and was told about the ramipril cardiac arrest. The patient’s doses were returned to original and furosemide titrated according to daily weight Zarowitz, BJ, Heart failure management and the war between evidence-based guidelines and common sense. Geriatr Nurs 2013; 34: 230 – 2.

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 To summarize, let me remind you once again that: 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, and Evidence-based medications and non-pharmacological interventions are an important part of improving the care of HF patients © Omnicare, Inc. 2013

Thank you for this opportunity!
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Pharmacologic Considerations for Reducing Hospital Readmission in Geriatric Patients with Heart Failure Barbara J. Zarowitz, Pharm.D. Chief Clinical Officer,

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Pharmacologic Considerations for Reducing Hospital Readmission in Geriatric Patients with Heart Failure Barbara J. Zarowitz, Pharm.D. Chief Clinical Officer,

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Presentation on theme: "Pharmacologic Considerations for Reducing Hospital Readmission in Geriatric Patients with Heart Failure Barbara J. Zarowitz, Pharm.D. Chief Clinical Officer,"— Presentation transcript:

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