Medication Therapy Management of the Patient with Congestive Heart Failure November 5, 2007 Joe Anderson, PharmD, PhC, B

1. Medication Therapy Management of the Patient with Congestive Heart Failure November 5, 2007 Joe Anderson, PharmD, PhC, BCPS Office: 272-3664 Email: janderson@salud.unm.edu College of Pharmacy University of New Mexico Health Sciences Center

2. Learning Objectives • List and understand the current guidelines for the management of chronic heart failure. • Assess the appropriateness of drug therapy for a patient with chronic heart failure. • Identify precipitating factors in heart failure, particularly drugs that may precipitate or exacerbate heart failure. • For a given patient with heart failure, recommend an appropriate pharmacotherapeutic plan. • Provide proper patient education regarding lifestyle modification for the patient with chronic heart failure.

3. Reading: • Hunt SA, Abraham WT, Chin MH. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). Circulation 2005;112:1-27. • Adams KF, Lindenfield J, Arnold JMO, et al. Executive Summary: HFSA 2006 Comprehensive Heart Failure Guideline. J Cardiac Failure 2006;12:10-38.

4. Definitions • Heart failure: a syndrome that exists when the heart is unable to pump sufficient blood to meet the metabolic needs of the body • Characterized by elevated cardiac filling pressures (preload) and or inadequate oxygen delivery, at rest or during stress, caused by cardiac dysfunction

5. Definitions: Systolic Dysfunction Systolic Dysfunction • an impairment of the contraction of left ventricle such that stoke volume (SV) is reduced for any given end-diastolic volume (EDV) or filling pressure. • Ejection fraction is reduced (< 45%) Left ventricular ejection fraction • SV/EDV • Normal: 50 - 70% • Objective measure of systolic function • Measured by • ECHO (Echocardiogram) • RNV (Radionuclide ventriculogram) • cardiac catheterization

8. Definitions: Diastolic Dysfunction • New Name: Heart failure with preserved left ventricular systolic function (or EF) • Ventricular filling rate (increased HR) and the extent of filling are reduced (decreased EDV) or a normal extent of filling is associated with an inappropriate rise in ventricular diastolic pressure. Normal EF is maintained.

9. HF in the US: Current Statistics • Prevalence: 4.9 million symptomatic patients • Incidence: ~550,000 new cases/year • 1% between the ages of 50 and 59 years; >10% over age 80 • 999,000 hospital discharges • Mortality: >51,000 deaths/year • Prevalence of HF in US is increasing American Heart Association. 2002Heart and Stroke Statistical Update. 2001. American Heart Association. Heart Disease and Stroke Statistics —2003 Update. Dallas, Tex: American Heart Association; 2002.

10. 12 10 10 8 6 4.7 3.5 4 2 0 1991 2000 2037* HF Prevalence Projections Heart Failure Patients in US (millions) *Rich M. J Am Geriatric Soc. 1997;45:968–974. American Heart Association. 2002Heart and Stroke Statistical Update. 2001. American Heart Association. Heart Disease and Stroke Statistics —2003 Update. Dallas, Tex: American Heart Association; 2002.

11. Causes of Heart FailureSystolic Dysfunction Dilated Cardiomyopathy • Ischemic disease • myocardial ischemia • myocardial infarction • Non-ischemic disease • Primary myocardial muscle dysfunction • valvular abnormalities • hypertension • structural damage and/or damage to myocardial walls

12. Neurohormonal Mechanism of CHF • Components • Endothelin • Vasopressin (ADH) • Atrial Natriuretic Peptide • Endothelium-Derived Relaxing Factor • RAAS • SNS

13. Neurohormonal Mechanism of CHF • Direct toxic effects of NE and AII • Arrhythmias • Apoptosis • Impaired diastolic filling • Increased myocardial energy demand • Increased pre- and afterload • Platelet aggregation • Desensitization to catecholamines

14. Decrease Cardiac Output • Renal Perfusion • SNS Activity • Renin • Contractility • HR • Angio I Angiotensinogen ACE Vasoconstriction • Angio II • Endothelin • Aldosterone Na+ / H2O Ventricular • SVR retention dilation (afterload) • LVEDV (preload) Atrial Distention Ventricular • Proinflammatory Cytokines (TNF, IL-6) hypertrophy ANP AVP

15. Pathologic Progression of CV Disease Coronary artery disease Arrhythmia Left ventricularinjury Hypertension Low ejectionfraction Pathologicremodeling Death Diabetes Cardiomyopathy Pump failure Valvular disease Symptoms:DyspneaFatigueEdema Chronicheartfailure • Neurohormonalstimulation • Endothelial dysfunction • Myocardial toxicity • Vasoconstriction • Renal sodium retention Adapted from Cohn JN. N Engl J Med. 1996;335:490–498.

16. Pathophysiology LV function LV impedence (afterload) Cardiac output + Salt/water retention (preload) Neurohormonal activation The Vicious Cycle of Heart Failure

17. Signs and Symptoms of Heart Failure

18. New York Heart Association Functional Classification I. No limitations of physical activity, no symptoms with ordinary activities II. Mild/slight limitation, symptoms with ordinary activities III. Moderate/marked limitation, symptoms with less than ordinary activities IV. Severe limitation, symptoms of heart failure at rest Symptoms: Dyspnea or fatigue Adapted from Criteria Committee of the New York Heart Association, 1994.

19. 4 Steps for pharmacists to decrease CHF mortality and morbidity 1 • Identify patients with heart failure and assess functional status • Educate and encourage lifestyle modification • Recommend optimal pharmacotherapy • Follow-up 2 3 4 Source: Joe Anderson’s logical thinking

20. 4 Steps for pharmacists to decrease CHF mortality and morbidity • Recent study documented benefits of a RPh to improve medication adherence in CHF patients • Patients randomized to interventional RPh or usual care • Interventional RPh provided additional education about CHF and medications • At 9 months adherence was 78.8% vs. 67.9%, which dissipated 3 months after completion of study • ER visits and Hospitalizations were decreased by 19% and annual direct healthcare costs were decreased by $2,960.00 per patient. Ann Intern Med. 2007;146:714-725.

21. Pharmacist Clinician: Evidence of Benefit • UNMH Congestive Heart Failure Clinic • Multi-disciplinary clinic (cardiologists, pharmacist clinicians, clinical nurse specialist, nurse case-manager) • PhC duties: interview patients, provide patient education, perform physical assessment, review laboratory and other diagnostic data, and formulate assessment and therapeutic plan

22. Pharmacist Clinician: Evidence of Benefit • Initial outcomes assessment of HFC performed in 2000 • First 35 patients enrolled in clinic • Patient outcomes compared from 1 yr prior to enrollment in HFC to 1 yr after enrollment • Outcomes: • Hospital admissions for heart failure • Patient functional class • Optimization of medication regimens • Health care costs

23. Pharmacist Clinician: Evidence of Benefit • Outcomes study results: • 91% reduction in CHF hospitalizations • Significant improvement in: • Patient’s level of functioning • Utilization of heart failure medications proven to reduce morbidity and mortality • Overall cost savings of $161,856/year or $4624/patient O’Connell AM et al. Am Heart J 2001;254-258.

24. Pharmacist Clinician: Evidence of Benefit ACE inhibitor/ARB and Beta-blocker utilization Leos C, et al. Presented at 2005 Western States Residents Conference, Monterrey, CA

25. Pharmacist Clinician: Evidence of Benefit • PMG PhC CHF Program • Savings Due to Decreased Admits • Cost savings from 1/1/2003 through 6/30/2003: $383,278.77 • Savings Due To Decreased ER Visits • Cost Savings from 1/1/2003 through 6/30/2003: $13,770

26. Step 1: Identifying the patient with heart failure • Identify patients receiving concomitant digoxin and furosemide or other loop diuretics. • Ask either the patient, their spouse or their caregiver. “Has your Dr told you that you have heart failure or a weakened heart or that your heart doesn’t pump as well as it use to?”

27. Step 1: Assess functional status Do you get winded or have trouble catching your breathwhen climbing a flight of stairs? Do you get winded when walking around your house orthe store? Do you ever get awakened at night by the sudden inabilityto catch your breath? Do you need to sleep with extra pillows in order to sleepcomfortably? Do you now sleep in a chair instead of sleeping in bed? Have you experienced any recent weight gain?

28. Step 2: Educate about Lifestyle modification • Make sure all your patients have a scale • Instruct patient to weigh and record first thing every morning after voiding • Patient should call their provider if weight increases by 2 lbs/day or 5 lbs/week.

29. Step 2: Educate about Lifestyle modification • Teach to “shake” the salt habit • No more than 2000 mg NaCl. • One level teaspoon has approximately 2000 mg. • Therefore no added salt to foods is best. • Enough sodium (salt) can be obtained from one’s diet without adding any table salt. • Careful with salt substitutes and potassium sparing meds!!

30. Step 2: Educate about Lifestyle modification • Emphasize the importance of exercise for improvement of symptoms and quality of life. • Encourage patient to consult physician about the appropriate type and amount of exercise.

31. Step 2: Educate about Lifestyle modification • Encourage weight loss, if overweight. • Smoking cessation Benefits include: • Decrease BP • Helps with exercise tolerance • Decreases risk of blood clots • Avoid alcohol • Moderate intake may be O.K.

32. Step 3: Recommend optimal pharmacotherapy Like most veterinary students, Doreen breezes through chapter 9.

33. ACC/AHA Guidelines • Class I: Conditions for which there is evidence and/or general agreement that a given procedure/therapy is useful and effective. • Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of performing the procedure/therapy. • Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy. • Class IIb: Usefulness/efficacy is less well established by evidence/opinion. Available at http://www.acc.org/clinical/guidelines/failure/index.pdf

34. ACC/AHA Guidelines • Class III: Conditions for which there is evidence and/or general agreement that a procedure/therapy is not useful/effective and in some cases may be harmful. • The levels of evidence upon which these recommendations are based were ranked as • Level A if the data were derived from multiple randomized clinical trials • Level B when data were derived from a single randomized trial or nonrandomized studies • Level C when the consensus opinion of experts was the primary source of recommendation. Available at http://www.acc.org/clinical/guidelines/failure/index.pdf

35. Ex. Pts with: previous MI, LV systolic dysfunction, asymptomatic valvular disease Ex. Pts with: HTN, CAD, DM, obesity, metabolic Sx, exposure to cardiotoxins, or a family history Ex. Pts with: known stuctural disease & SOB, fatigue, reduced exercise tolerance Pts with marked Sxs at rest despite maximal medical tx, recurrent hospitalizations Stage A High risk for HF but no Sx’s or stuctural heart disease Stage B Stuctural heart disease but no Sx’s of HF Stage C Stuctural heart disease with prior or current Sx’s of HF Stage D Refractory HF requiring specialized interventions Therapy -All in Stage A & B -Drugs for routine use: Diuretics (if  fluid) ACEIs BBs -Dietary sodium restriction Selected Patients: ARBs, aldosterone antagonist, digoxin, hyd/ntg Devices (BiV pacing, ICD) Therapy -All in Stage A, B, & C -Mechanical assist devices -Heart transplantation -Continuous IV inotropic infusions -Hospice care Therapy -All in Stage A -ACEI/ARB for appropriate pts -BB’s for appropriate pts Therapy -Tx HTN -Smoking cessation -Tx lipids -Regular exercise -d/c ETOH -d/c illicit drugs -ACEI’s/ARB for high risk pts Available at http://www.acc.org/clinical/guidelines/failure/index.pdf

36. ACC/AHA Guidelines: Diuretics • No data regarding morbidity or mortality • Class I: Diuretics and salt restriction are indicated in patients with current or prior symptoms of HF and reduced LVEF who have evidence of fluid retention. (Level of Evidence: C) Available at http://www.acc.org/clinical/guidelines/failure/index.pdf

37. Pharmacotherapy: Diuretics • Decrease Preload • Thiazides can be used if GFR>30ml/min • Work on distal tubule • Loop diuretics • Ascending loop of henle • Dosed once or twice daily • Resistance: Use combination therapy • Monitor K+ , Mg2+, BUN, and SCr

38. Pharmacotherapy: Diuretics • Keep K+ between 4.0 to 5.0 meq/L • Supplement Mg2+ if < 1.6 meq/L • Back down dose if hypotensive or evidence of azotemia (BUN/CR > 20)

39. Diuretic Resistance Proximal Tubule Distal Tubule NaHCO3 Thiazides X Collecting tubule X Ca2+ Spironolactone X Acetazolamide X NaCl Na+ (Aldosterone) Mg2+ K+ 2CL- Loop Diuretics H2O (ADH) K+ H+ Loop of Henle

40. Digoxin • (+) inotrope, decreases ventricular rate, possibly some NH modulation • Monitor serum levels if toxicity or noncompliance suspected, or if renal function or interacting drugs added

41. Digoxin • DIG trial (N Engl J Med 1997:336:525-33) • No survival benefit versus placebo •  CV and CHF hospitalizations by 8% and 23%, respectively (p<0.001) ACC/AHA Recommendation • Class IIa: Digitalis can be beneficial in patients with current or prior symptoms of HF and reduced LVEF to decrease hospitalizations for HF. (Level of Evidence: B) “…digitalis does not compare favorably with such agents as the aldosterone blockers…The Writing Committee, therefore, decided to change the level of recommendation for digitalis glycosides from Class I to Class IIa…” Available at http://www.acc.org/clinical/guidelines/failure/index.pdf

42. Digoxin • Low dose sufficient 0.125 mg/d • Inotropic effects seen at low concentrations (0.5 – 0.8 ng/mL) (NEJM 2002; 347:1403-11) • Women may not derive benefit “The conflicting data regarding the efficacy of digoxin in women suggests that if it is prescribed, particular attention should be paid to dosing and renal function.” Available at http://www.acc.org/clinical/guidelines/failure/index.pdf J Am Coll Cardiol 2005;46:497-504.

43. Effects of Angiotensin II Elevation in CHF

44. RAA System - During ACE Inhibition Angiotensinogen Renin Inactive Compounds t-PA Cathepsin G Angiotensin I Chymase CAGE ACE Angiotensin II Bradykinin AT2 receptor AT1 receptor Bradykinin2 receptor VasodilationInhibition of Vascular and Myocardial Hypertrophy VasoconstrictionCell GrowthSodium and Fluid Retention Sympathetic Activation VasodilationImproved Endothelial FunctionAntiproliferative Effect

45. Effect of ACE Inhibitors on Mortality Reduction in Patients With Heart Failure Mortality Trial ACEI Controls RR (95% CI) Chronic CHF CONSENSUS I 39% 54% 0.56 (0.34–0.91) SOLVD (Treatment) 35% 40% 0.82 (0.70–0.97) SOLVD (Prevention) 15% 16% 0.92 (0.79–1.08) Post MI SAVE 20% 25% 0.81 (0.68–0.97) AIRE 17% 23% 0.73 (0.60–0.89) TRACE 35% 42% 0.78 (0.67–0.91) SMILE 5% 6.5% 0.75 (0.40–1.11) Average 21% 25%

46. ACEI: Dosing Drug Initial Dose Target Dose Enalapril* 2.5 mg BID 10 mg BID Captopril* 6.25-12.5 mg TID 50 mg TID Lisinopril* 5 mg QD 20 mg QD Quinapril 5 mg BID 20 mg BID Ramipril* 1.25-2.5 mg BID 5 mg BID Fosinopril 5-10 mg QD 20 mg QD *Clinical trial evidence of decreased CHF morbididty/mortality

47. High dose ACE-inhibitor treatment • ATLAS study compared “high” and “low” dose lisinopril for effects on mortality. • No difference in mortality. • High-dose reduced hospitalizations for any cause (-13%) and for heart failure (-24%); p<0.05. Packer M, et al. Circulation 1999;100:2312.

48. ACC/AHA Guidelines: ACE inhibitors Class I: ACE Inhibitors are recommended for all patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated. (Level of Evidence: A) Available at http://www.acc.org/clinical/guidelines/failure/index.pdf

49. ACE-I in CHF: Precautions • Renal Impairment • Hyperkalemia • Hypotension • Cough *Patients should be seen in 1 – 2 weeks to monitor their serum Cr, K+, and B.P.

50. Step 3: Recommend optimal pharmacotherapy • ACE Inhibitors for all patients • Initial dose 1/2 usual: SBP < 100 mmHg, SCr > 2.0 mg/dL, Na < 130 mg/dL • Try to achieve target dose but not at the expense of beta-blocker therapy • ASA may interfere with efficacy, recommend low-dose ASA (< 160 mg) if necessary • Recommend f/u in 1 - 2 weeks to check BP, BUN/SCr, and K+.