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:
1 Pharmacologic Considerations for Reducing Hospital Readmission in Geriatric Patients with Heart FailureBarbara J. Zarowitz, Pharm.D.Chief Clinical Officer, Vice President of Clinical ServicesOmnicare, Inc., andAdjunct Professor of Pharmacy PracticeCollege of Pharmacy and Health SciencesWayne State UniversityNovember 2013
3 DisclosuresDr. Zarowitz is an employee of Omnicare, Inc., and holds Omnicare stockShe has been awarded numerous research grants for Omnicare Senior Health Outcomes from:AbbVieAmgenAstellasAvanirGlaxoSmithKlineMylanOptimerSanofi-aventisSavient
5 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 weeksMedicationDoseFrequencyaspirin EC81 mgonce dailyclopidogrel75 mgfurosemide40 mgmetoprolol50 mgtwice dailymirtazapine30 mgat bedtimezolpidem5 mgsimvastatinspironolactone25 mgdigoxinmgVitamin D31,000 units (2 tabs)Vitamin E400 unitslatanoprost1 drop each eyewt ≤ 162 = no dosewt , 1 tab40 mg (2 tabs)wt 168, 2 tabswt 169, 2 tabs twice daily40 mg (4 tabs)wt 170, 2 tabs twice dailyBP-90/64, HR-100, RR-20, T-98.6PMH: NYHA stage IV HF, glaucoma, coronary artery disease, hypertension, ocular strokesHPI: hospitalized the previous year twice for syncope associated with heart failure. Cardiac arrest during one hospitalization following administration of ramipril 2.5 mgCXR: no infiltratesLabs: WBC – wnl
6 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
8 Pathophysiology of Heart Failure Causal FactorsMyocardial DamageMyocardial FailureCardiac outputLV end diastolic pressureSVR (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 ResponsesRAA SNS ANFVasopressin
12 Heart Failure in the Elderly Persons older than 65 years account for 80% of heart failure hospitalizationsPrevalence doubles with each decade of life over age 75About 6% to 10% over 65 years have heart failure88% of newly diagnosed cases occur in patients older than 65 years49% are older than 80 yearsThe 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 yearsAmerican 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:
13 Coronary artery disease Features Distinguishing Heart Failure in the Elderly from Heart Failure Occurring During Middle AgeMiddle AgeElderly(≥ 65 years)Prevalence<1%≈10%GenderM > FF > MEtiologyCoronary artery diseaseHypertensionLVEFReducedNormalComorbiditiesFewMultipleRCTsManyTherapyEvidence-basedEmpiricPhysicianCardiologistPrimary careM=male; F=female; LVEF=left ventricular ejection fraction; RCT=randomized clinical trialThe 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:
14 Pharmacokinetic and Pharmacodynamic Variants in Older Persons with Heart Failure AbsorptionIncreased gastric pH, delayed gastric emptying, reduced GI blood flow and slowed intestinal transitDecreased bioavailability of medications with acid-dependent absorption (iron) and slowed absorption of medications, especially those that are enteric coatedMetabolism20 – 30% reduction in liver mass and hepatic blood flow but hepatocytes remain intactCYP isozymes may be decreased but do not necessarily result in reduced clearancefirst-pass metabolism is reduced with ageEliminationClcr declines progressively with age mL/min/yearPhysiologic 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.2As 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.
17 Risk Factors for Heart Failure Strongly and consistently associated with HFLess consistentlyassociated with HFAgeMale sexHypertensionElectrocardiographic LV hypertrophyMyocardial infarctionDiabetesValve diseaseOverweight/obesityExcessive alcohol consumptionSmokingDyslipidemiaRenal insufficiencySleep-disordered breathingLow physical activityLow socioeconomic statusCoffee consumptionDietary sodium intakeIncreased heart rateImpaired pulmonary functionMental stress and depressionProspective 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;
18 Medications That May Exacerbate Heart Failure AgentsRationaleAntiarrhythmic agents (avoid disopyramide and flecanide; amiodarone and dofetilide are acceptable, if necessary, for arrhythmia)Calcium channel antagonists (diltiazem, verapamil)ItraconazoleTerbinafineNegative inotropic effectsAlcohol (excessive amounts in predisposed patients)DoxorubicinDaunomycinCyclophosphamideCardiotoxicAndrogensCOX-2 inhibitorsEstrogensGlucocorticoidsNonsteroidal anti-inflammatory drugsSalicylates (high doses)Sodium-containing drugs (e.g., ticarcillin)Thiazolidinediones (rosiglitazone, pioglitazone)Sodium and waterretentionAlbuminBlood productsOsmotic agentsA 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
20 Congestive Heart Failure Large left ventricleThickening of the interlobular septa – Kerley B linesPeribronchial cuffing – wall is normally hairline thinThickening of the fissures – fluid in the subpleural space in continuity with interlobular septaPleural effusions
23 BNP Diagnostic Algorithm DyspneaPhysical Examination, Chest XR, ECG, BNP LevelBNP <100pg/mlBNP pg/mlBNP >400pg/mlBaseline LV Dysfunction,Underlying Cor Pulmonale,Or Acute Pulmonary EmbolismBNP 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%)YesNoPossible Exacerbation of CHF (25%)CHF Likely(75%)Adapted from: Tabbibizar R, Maisel A. Curr Opin Cardiol. 2002;17:343.
24 BNP concentration for the degree of heart failure severity BNP for DiagnosisBNP concentration for the degree of heart failure severityBNP 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 = 27n = 34n = 36Maisel A et al. J Am Coll Cardiol 2001;37(2)
25 Evidence-Based Treatment Guidelines Yancy CW, et al ACCF/AHA Heart Failure GuidelinesJessup M, et al ACCF/AHA guidelines for the diagnosis and managementof heart failure in adults. Circulation ;119:1977–2016.
31 Medications That May Cause or Exacerbate HF* AgentsHow they cause/exacerbate HFAntiarrhythmics† [e.g., Multaq (dronedarone), Rythmol (propafenone), Tambocor (flecanide)]Non-dihydropyridine Calcium Channel Blockers [e.g., Calan or Isoptin (verapamil) or Cardizem (diltiazem)]Itraconazole or TerbinafineNegative inotropic effects (decrease the force of the hearts contraction)Alcohol (excessive amounts)Some chemotherapy treatments (e.g., doxorubicin, daunomycin, cyclophosphamide)CardiotoxicAndrogens or EstrogensAspirin (high doses)NSAIDs (e.g., celecoxib, ibuprofen, meloxicam, naproxen)Glucocorticoids (e.g., prednisone)Thiazolidinediones [e.g., pioglitazone, Avandia (rosiglitazone)]Sodium and water retentionAlbuminBlood products (e.g., transfusion)Osmotic agentsIn 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
35 A.C.E. Kininase II ACE-I: Mechanism of Action VASOCONSTRICTION VASODILATATIONALDOSTERONEPROSTAGLANDINSVASOPRESSINKininogentPASYMPATHETICKallikreinAngiotensinogenRENINBRADYKININAngiotensin IACE-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: AccessedA.C.E.InhibitorKininase IIANGIOTENSIN IIInactive Fragments
36 ACE Inhibitors RISKS BENEFITS Hypotension Prolonged survival* Renal dysfunctionHyperkalemiaCoughAngioedemaNeutropeniaProlonged survival*Clinical improvementMore stable clinical courseFewer hospitalizationsSlower disease progressionAs 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
37 ACE Inhibitors: Indications and Doses AgentHFLV DysfunctionInitial DoseMaximum Dosecaptopril (Capoten®) (post-MI)6.25 mg tid50 mg tidenalapril (Vasotec®) (asymptomatic)2.5 mg bid10 – 20 mg bidfosinopril (Monopril®)NAmg qd40 mg qdlisinopril (Prinivil®, Zestril®)mg qd20 – 40 mg bidquinapril (Accupril®)10 mg bid40 mg bidramipril (Altace®)1.25 – 2.5mg qd10 mg qdtrandolapril (Mavik®)1 mg qd4 mg qdThis 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 ventricularHF = heart failure, MI = myocardial infarction
38 ACE Inhibitors, Heart Failure, and Mortality Reduction STUDYACE-IPatientsDurationResultsCONSENSUSMean age 71Enalaprilmg/d vs. placeboN=253Class IV HF12 months6 month mortality ↓ 40%1 year mortality ↓ 31%Death from progressive HF ↓ 50%SOLVDMean age 6010 mg bid vs. placeboN=2,589EF < 35%42 months3.5 year mortality ↓ 16%Death or CHF hospitalization ↓26%CV hospitalization ↓ 10%AIREMean age 65Ramipril2.5-5 mg bidN=2,006HF post MI30 monthsAll cause mortality ↓ 17%Risk of 1st event ↓ 19%SAVECaptoprilmg/d vs. placeboN=2,231EF < 40%Post MIAll 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.
39 ATLAS Trial Low-dose vs. high dose lisinopril N = 3,164 2.5 to 5 mg QD or 32.5 to 35 mg qdN = 3,164Average age 63.6 yearsNYHA II-IVEF ≤ 30%High dose group had:12% lower risk of death or hospitalization for any reason (P=0.002) for high24% 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:
40 CONSENSUS Trial Placebo Enalapril Probability of death Months 0.8 0.7 0.6p< 0.0010.5Probability of death0.4p< 0.0020.3EnalaprilCONSENSUS=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;316:0.20.1123456789101112MonthsCONSENSUS. N Engl J Med 1987;316:
41 SOLVD Trial (Treatment Arm) 0.8PlaceboPlacebon=12840.70.6p< 0.0010.5p =p< 0.002Enalapriln=1285Percent Survival0.4Enalapril0.3SOLVD=Studies of Left Ventricular DysfunctionSOLVD 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;325:0.2n = 2589CHF- NYHA II-III- EF < 350.16121824303642MonthsSOLVD. N Engl J Med 1991;325:
42 ACE Inhibitors: Contraindications/ Risk-Benefit Considerations Known bilateral renal artery stenosisHistory of angioedemaPregnancyRisk-benefit considerationsSystolic blood pressure < 90 mm HgSerum creatinine > 3 mg/dLSerum potassium > 5.5 mEq/mLThere 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
44 Angiotensin I ANGIOTENSIN II Angiotensin II ReceptorBlockers (ARB): Mechanism of ActionRENINAngiotensinogenAngiotensin I ANGIOTENSIN IIACEOther pathwaysAT1ReceptorBlockersRECEPTORSAngiotensin 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: AccessedAT1AT2VasoconstrictionProliferativeActionVasodilatationAntiproliferativeAction
45 ACC/AHA Guidelines on the Role of ARBs in HF Therapy Several clinical trials with ARBs failed to show mortality benefit in heart failureARBs should not be considered equivalent or superior to ACE inhibitors in the treatment of HFARBs should not be used for the treatment of HF in patients who have had no prior use of an ACE inhibitorARBs 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 hyperkalemia2013 ACCF/AHA Heart Failure Guidelines . J Am Coll Cardiol.
46 Val-HeFT: Comparison of Event Rates Valsartan(%)PlaceboRR*pAll-cause mortality17.327.10.670.017Morbidity/mortality24.942.50.56<0.001Cardiovascular death15.722.10.760.074Sudden death with resuscitation0.51.10.460.529Hospital admission for HF13.026.50.47When 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:
47 CHARM Trial 3 studies in one CHARM-Alternative: LVEF ≤ 40% and could not tolerate an ACE inhibitorCHARM-Added: LVEF ≤ 40% who were currently taking an ACE inhibitor, with or without a beta-blockerCHARM-Preserved: LVEF > 40%Overall-- showed ARB beneficial in terms of morbidity and mortality in heart failureThe 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.
48 Combination of ACEI and ARB in Heart Failure Management Relative Risk of DeathBackground TherapyNACEI +, Beta BlockerACEI +, Beta BlockerACEI -, Beta BlockerACEI -, Beta BlockerIn 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;345:1.0Valsartan BetterPlacebo BetterP=0.009Test for heterogeneityCohn JN et al. NEJM 2001;345:
49 All-Cause Mortality in the VALIANT Study GroupAll-cause mortality (%)Hazard ratio (95% CI)compared with captoprilp valueCaptopril (n=4909)19.5-Valsartan (n=4909)19.91( )0.98Combination (n=4885)19.3( )0.73VALIANT = valsartan in Acute Myocardial InfarctionThis 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:
50 VALIANT: Cardiovascular Death, Recurrent MI, or Heart Failure Hospitalization Secondary End PointGroupCV death, re-MI, or heart-failure hospitalization (%)Hazard ratio (95% CI) compared with captoprilp valueCaptopril (n=4909)31.9-Valsartan (n=4909)31.10.95( )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 significantPfeffer MA et al. N Engl J Med 2003; 349:
51 VALIANT: Incidence of Adverse Events GroupAny adverse event (%)AnyADE leading to permanent study drug discontinuation (%)Captopril28.47.7Valsartan29.45.8*Combination34.8*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:
52 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 toleratedTitrate no sooner than every 2 weeksMay initially worsen HF and may need to adjust diuretics to maintain pre-treatment weightMonitor heart rate and blood pressureTypically held if pulse <60 beats per minuteMonitor for hypoglycemia if diabeticMay block symptoms of hypoglycemia except sweatingCarefully assess risk vs. benefit for patients with:Reactive airway disease (e.g., asthma)COPDPeripheral vascular diseaseThe 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.
53 Dosages of Beta-Blockers in Heart Failure DrugStarting DosageTitration Sequence*Maximum DosageBisoprolol(Zebeta®)1.25 mg/dayIncrease to 2.5 mg/day in 2-4 weeks, then increase to 5.0 mg/day in 2-4, weeks, then increase to maximum10 mg/dayCarvedilol (Coreg®)3.125 mg twice dailyIncrease to 6.25 mg bid in 2-4 weeks, then increase to 12.5 mg bid in 2-4 weeks, then increase to maximum25 mg twice daily (50 mg twice daily if > 85 kg)Metoprolol extended release (Toprol XL®)12.5 mg/dayIncrease 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 maximum200 mg/dayA 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: AccessedFarrell 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:
54 Diuretics (furosemide, bumetanide, hydrochlorothiazide,metolazone) Reduce fluid volume to decrease workload of the heartLoop diuretics (e.g., furosemide) are generally more effective than thiazide diuretics (e.g., hydrochlorothiazide)Thiazides are less effective with declining kidney functionAssess edema and monitor weight frequentlyOften requires use/adjustment of potassium supplementationMonitor electrolytes and kidney function routinelyMonitor for rash/photosensitivityCombination therapy with a loop and thiazide diuretic may be necessary in the presence of diuretic resistanceBoth 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
55 Inhibit reabsorption of Na in distal convoluted and collecting tubule Action of DiureticsThiazidesInhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of HenleCORTEXK-sparingInhibit reabsorption of Na in distal convoluted and collecting tubuleMEDULLALoop DiureticsInhibit exchange of Cl-Na-K in thick segment of the ascending loop of HenleDiuretics 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: AccessedLoop of HenleCollecting Tubule
56 Loop Diuretics Mechanism of action Adverse reactions Act on the ascending limb of loop of HenleIncrease potassium, magnesium and calcium excretionMore effective than thiazide diureticsAdverse reactionsElectrolyte/metabolic disturbanceshypokalemia, hypomagnesemia, hyperglycemia, hyperuricemiaMetabolic alkalosisAzotemiaHypotension, including orthostasisOtotoxicityOther (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: AccessedKubo SH et al. Am J Cardiol 1987;60:1322MRFIT. JAMA 1982;248:1465
57 Thiazide Diuretics Mechanism of action Adverse reactions No dose responseIncrease potassium, magnesium and calcium excretion more than with loop diureticsIncrease renal vasoconstrictionIncrease uric acid excretionAdverse reactionsElectrolyte/metabolic disturbanceshypokalemia, hypomagnesemia, hyperglycemia, hyperuricemiaMetabolic alkalosisAzotemiaHypotension, including orthostasisOther (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: AccessedSharpe N. Heart failure. Martin Dunitz 2000;43Kubo SH , et al. Am J Cardiol 1987;60:1322MRFIT, JAMA 1982;248:1465Pool Wilson. Heart failure. Churchill Livinston 1997;635
58 Torsemide Loop diuretic Consistent absorption Reduced fatigue Fewer hospitalizationsLower cost of careCompared 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:
59 Diuretic Resistance: Causes Delayed absorption of the diureticReduced secretion of the diuretic into the tubular lumen (its site of action)Compensatory retention of sodium after the effective period of the diureticHypertrophy and hyperplasia of epithelial cells of the distal convoluted tubuleIn 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:
60 Diuretic Resistance: Management Rule out non-complianceDose adjustmentIntravenous bolus injection or continuous infusion of a loop diureticCombination diuretic therapyMetolazone use in combination with loopsGiven 30 minutes prior to loop administrationMonitor closely for hypokalemiaThe 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:
61 DigoxinIncreases 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 doseMonitor pulse prior to giving each doseMonitor for signs/symptoms of toxicity (nausea, anorexia, visual disturbances, electrolyte abnormalities, impaired cognition, weakness, dizziness, hallucinations, etc)Monitor BMP and digoxin concentration routinelySerum drug concentration of ng/mL is the recommended therapeutic rangeAlthough 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.
62 Digoxin Inhibits sodium-potassium adenosine triphosphatase Promotes calcium influx via sodium-calcium exchange mechanismResults in an increase in the contractile state of the heartStroke volume and cardiac output increaseIndirect increase in parasympathetic toneResults in decrease in heart rateDirect and indirect decrease in sympathetic toneSecondary to impaired cardiac outputIndirectly decreases sympathetic vasoconstrictionDigitalis 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
63 Digoxin: Mechanism of Action -Na-Ca ExchangeNa-K ATPaseNa+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: AccessedMyofilamentsCa++K+Na+CONTRACTILITY
64 Digoxin: Clinical UseTherapy is initiated at dose of mg for heart failureLower doses such as every other daySome elderlyImpaired renal functionCaution in patients with significant sinus or atrioventricular blockNot indicated for stabilization of acute decompensated heart failureDigitalis 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.
65 Serum Digoxin Concentrations Are lower digoxin concentrations effective?MethodsData from PROVED and RADIANCEBoth were randomized, multi-center, double-blind clinical trialsPROVED – diuretic vs. diuretic + digoxinRADIANCE – ACEI+diuretic vs. ACEI+diuretic+digoxinCompared digoxin withdrawal vs. continuation for worsening heart failureSerum drug concentration (SDCs) obtained at baseline, 4, 8, and 20 weeksAdams 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:
66 Risk of Treatment Failure Based on Randomization SDC Group Treatment GroupRelative Risk95% CIP ValueDigoxin concentration(SDC)< 0.9 ng/ml0.090.018> ng/ml0.220.004> 1.2 ng/ml0.17<0.001These 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 concentrationAdams KF et al. J Am Coll Cardiol 2002;39:
67 Digoxin: Clinical Trials Digitalis Investigation Group (DIG Trial)6,800 patients with ischemic and non-ischemic cardiomyopathyMild to moderate heart failureRandomized to placebo or digoxinDigoxin has no effect on mortalityDigoxin 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 harmfulSDCs of ~ 1.0 ng/mL may not provide any clinical benefit vs. placeboSDC of 0.5 to 0.8 ng/mL likely the optimal therapeutic rangeThe 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:
68 DIG Clinical Trial Percent Mortality Months 50 40 30 20 10 Placebo PlaceboN=3403Percent MortalityP=0.8The 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:DigoxinN=3397n = 6800NYHA II-III12243648MonthsThe Digitalis Investigation Group. N Engl J Med 1997;336:
69 Digoxin Concerns in the Elderly Narrow therapeutic indexAge related decrease in renal functionResults in increased serum digoxin concentrationsMay cause deliriumDrug-drug interactionsAffect digoxin bioavailability or excretionIncrease risk of digoxin toxicityReduced skeletal massReduced volume of digoxin distributionDigoxin 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:
70 Absolute diff. between sexes (%)* Digoxin and WomenOutcomeWomen digoxin(%)WomenPlacebopAbsolute diff. between sexes (%)*Death from any cause33.128.90.0785.8Death from CV causes27.824.10.0984.3Death from worsening HF12.411.90.7502.8Hospitalization for worsening HF30.234.40.0794.7To 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:
71 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 womenK+ should be 5.0 mEq/LEplerenone is NOT suggested for those over 75 years of age due to lack of survival benefitMonitor BMP and kidney function routinelyMinimize concomitant use of potassium supplements, especially in combination with an ACEI or ARBMonitor 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
72 Aldosterone Antagonists: Mechanism of Action SpironolactoneALDOSTERONECompetitive antagonist of thealdosterone receptor(myocardium, arterial walls, kidney)CollagendepositionFibrosis- myocardium- vesselsRetention Na+Retention H2OExcretion K+Excretion Mg2+EdemaAldosterone 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: AccessedArrhythmias
73 Spironolactone: Indications Recent or current symptoms despite ACEI, diuretics, digoxin, and beta-blockersRecommended in advanced heart failure (II-IV), LVEF of ≤ 35%, in addition to ACEI and diureticsHypokalemia-ESC HF guidelines 20012013 ACCF/AHA guidelines
74 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 HFPitt 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:
75 RALES Trial: Spironolactone Annual MortalityAldactone 18%; Placebo 23%1.00.90.80.70.60.5SurvivalAldactonep <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 = 1663NYHA III-IVMean follow-up 2 yPlacebo61218243036RALES. N Engl J Med 1999;341:709months
76 RALES Results – patients with HF Before RALESAfter RALESEarly 1994(per 1000)Early 1999Late 2001Spiro Rx’s3430149*Hyper K+ adms2.44.011*Hyper K+ deaths0.30.72.0*(*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:
77 Spironolactone: Contraindications/ Risk-Benefit Considerations Potassium concentration > 5.5 mEq/LRisk-benefit considerationsConcomitant use with potassium supplementsLife threatening hyperkalemia when used with ACE inhibitors or ARBsCaregivers 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:
78 Eplerenone Potassium-sparing diuretic Lower affinity than spironolactone for progesterone and androgen receptorsEphesus trial showed statistically significant reduction in death versus placeboMore expensive than spironolactoneThose over 75 years did not respond to treatmentPitt 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
79 Hydralazine/Isosorbide Dinitrate Hydralazine is a peripheral arterial vasodilatorIsosorbide is a peripheral venous vasodilatorWorking 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 headachesThis 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 guidelines79
80 Inotropic Support [e.g., Dopamine, Dobutamine, Milrinone (Primacor®) Increase force of cardiac contractionMay provide symptom improvement but result in overall increase in mortalityCentral line access requiredMonitor for:HypotensionArrhythmiasDizziness/HeadacheAdequate fluid intakePeripheral blood perfusionThe 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
81 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 performanceContinuous 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 transplantationPalliative therapy in stage D despite optimal medication therapy and device therapy who are not eligible for MCS or transplantationPotentially Harmful – absence of specific indications noted above2013 ACCF/AHA guidelines
82 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
86 Heart Failure Clinics Dedicated clinics to heart failure Nurse practitioner trained in heart failureGreater access to a clinician“Brittle” patients need periodic medication adjustmentsCheaperReduces repeat hospitalizationsReduces morbidity and mortalityDedicated 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.
87 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.
89 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 weeksBP-90/64, HR-100, RR-20, T-98.6PMH: NYHA stage IV HF, glaucoma, coronary artery disease, hypertension, ocular strokesHPI: hospitalized the previous year twice for syncope associated with heart failure. Cardiac arrest during one hospitalization following administration of ramipril 2.5 mgCXR: no infiltratesLabs: WBC – wnlMedicationDoseFrequencyaspirin EC81 mgonce dailyclopidogrel75 mgfurosemide40 mgmetoprolol50 mgtwice dailymirtazapine30 mgat bedtimezolpidem5 mgsimvastatinspironolactone25 mgdigoxinmgVitamin D31,000 units (2 tabs)Vitamin E400 unitslatanoprost1 drop each eyewt ≤ 162 = no dosewt , 1 tab40 mg (2 tabs)wt 168, 2 tabswt 169, 2 tabs twice daily40 mg (4 tabs)wt 170, 2 tabs twice daily
90 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 infectionThe 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 weightZarowitz, BJ, Heart failure management and the war between evidence-based guidelines and common sense. Geriatr Nurs 2013; 34: 230 – 2.