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Saturday, March 24 - Interrupting the Revolving Door of Chronic Heart Failure

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Interrupting the Revolving Door of Chronic Heart Failure
0006-0000-18-007-L01-P | .2 CEUs |
Marcus Ravnan, PharmD, FCSHP, FASHP

Published in: Health & Medicine
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Saturday, March 24 - Interrupting the Revolving Door of Chronic Heart Failure

  1. 1. Interrupting the Revolving Door of Chronic Heart Failure Marcus C. Ravnan, Pharm.D., FCSHP, FASHP Professor, Department of Pharmacy Practice Assistant Dean, Office of Pre-Pharmacy & Pre-Health Affairs University of the Pacific Thomas J. Long School of Pharmacy and Health Sciences
  2. 2. Disclosure of Interest In preparing this presentation, I disclose that there are no potentially biasing relationships of a professional or personal nature that exist related to the content or direction of this educational presentation. I have no relevant financial interests or other relationships with the manufacturer(s) of commercial products and/or provider(s) of commercial services discussed in this educational presentation.
  3. 3. Program Objectives: - Describe the heart failure landscape, including prevalence, incidence, re-admission and mortality rates. - Evaluate the safety, efficacy, and mechanism of action of pharmacologic agents, both old and new and their impact on heart failure outcomes. - Assess evidence supporting the use and application of novel therapies in todays clinical practice. - Outline the pharmacists role in transitions of care that support improving patient outcomes
  4. 4. • 2011 to 2014 - 6.5 million Americans carried a HF diagnosis • It is projected that by 2030 – over 8 million Americans will carry the diagnosis • The care environment is currently seeing 960,000 new HF cases annually • Lifetime risk 20-45% age 45-95 years • Age is associated with the greatest disease-related incidence • 9.2 per 1000 age 65-74 • 22.3 per 1000 age 75-84 • 43.0 per 1000 age >85 • Heart Disease and Stroke Statistics – 2017 Update. Circulation. 2017;135:e146-603. • Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail. 2013;6:606–619. The current disease landscape
  5. 5. • Current projections reveal survival after onset has improved slightly attributed to evidence-based therapeutic management • Mortality remains high ~50% within 5 years of diagnosis • Hospitalization remains high • Within 1-year of diagnosis, 83% of patients expected to be hospitalized at least once, 43% at least 4 times • Case fatality rate within 30 days of hospital admission is 10.4% • Heart Disease and Stroke Statistics – 2017 Update. Circulation. 2017;135:e146-603. • Gerber Y, Weston SA, Redfield MM, et al. A contemporary appraisal of the heart failure epidemic in Olmsted County, Minnesota, 2000 to 2010. JAMA Intern Med. 2015;175:996–1004. • Chen J, Normand SL, Wang Y, Krumholz HM. National and regional trends in heart failure hospitalization and mortality rates for Medicare beneficiaries, 1998-2008. JAMA. 2011;306:1669–1678.
  6. 6. Why are HF Patients Hospitalized? • Pneumonia/Respiratory Related • Arrhythmia • Worsening renal function • Edema/Weight gain • Dyspnea • Medication related issue • Hypertension Precipitating Clinical Factors, Heart Failure Characterization, and Outcomes in Patients Hospitalized With Heart Failure With Reduced, Borderline, and Preserved Ejection Fraction. Kapoor JR, Kapoor R, Ju C, et al. JACC Heart Fail. 2016;4(6):464-472.
  7. 7. Projected Direct Costs of Cardiovascular Disease Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123:933–944.
  8. 8. Syndrome of Structural and Functional impairment  Abnormal ventricular function  Inadequate tissue perfusion  Intravascular & Interstitial volume overload What is Heart Failure?
  9. 9. The sequelae  Renal Hemodynamics  Vascular Hemodynamics  Compensatory Systems  Myocardial Dynamics  Inflammation and Immune Activation  Tissue Metabolism, Energy Utilization & Delivery
  10. 10. The complexity of the sequelae Katz M. Pathophysiology of heart failure: identifying targets for pharmacotherapy Med Clin North Am. 2003 Mar;87(2):303-16.
  11. 11. Simplified View •Briasoulis, A., Androulakis, E., Christophides, T. et al. Heart Fail Rev (2016) 21: 169. •Robert J. Mentz, Christopher M. O'Connor. Nature Reviews Cardiology volume 13,pages 28–35 (2016).
  12. 12. Types of Heart Failure • Systolic (or squeezing) heart failure – Decreased pumping function of the heart, which results in fluid back up in the lungs and heart failure • Diastolic (or relaxation) heart failure – Involves a thickened and stiff heart muscle – As a result, the heart does not fill with blood properly – This results in fluid backup in the lungs and heart failure
  13. 13. Categorization based on cardiac function HFpEF HFrEF
  14. 14. Risk Factors for Heart Failure • Coronary artery disease • Hypertension (LVH) • Diabetes • Smoking History • Myocardial Infarction • Obesity • Advanced Age • Alcoholism • Valvular heart disease • Congenital heart defects • Arrhythmias • COPD • Other: – Anemia – Obstructive Sleep Apnea – Connective tissue diseases – Toxins
  15. 15. Treatment; When where you have been is just as important as where you are headed
  16. 16. Too often therapy overlooks risk factors • Coronary artery disease • Hypertension (LVH) • Diabetes • Smoking History • Myocardial Infarction • Obesity • Advanced Age • Alcoholism • Valvular heart disease • Congenital heart defects • Arrhythmias • COPD • Other: – Anemia – Obstructive Sleep Apnea – Connective tissue diseases – Toxins
  17. 17. Compensatory Mechanisms: Renin-Angiotensin-Aldosterone System Renin + Angiotensinogen Angiotensin I Angiotensin II Peripheral Vasoconstriction  Afterload  Cardiac Output Heart Failure  Cardiac Workload  Preload  Plasma Volume Salt & Water Retention Edema Aldosterone Secretion ACE Kaliuresis Beta Stimulation • CO • Na+ Fibrosis
  18. 18. Guideline Approach Stages and Treatment of HF STAGE A At high risk for HF but without structural heart disease or symptoms of HF STAGE B Structural heart disease but without signs or symptoms of HF THERAPY Goals · Control symptoms · Improve HRQOL · Prevent hospitalization · Prevent mortality Strategies · Identification of comorbidities Treatment · Diuresis to relieve symptoms of congestion · Follow guideline driven indications for comorbidities, e.g., HTN, AF, CAD, DM · Revascularization or valvular surgery as appropriate STAGE C Structural heart disease with prior or current symptoms of HF THERAPY Goals · Control symptoms · Patient education · Prevent hospitalization · Prevent mortality Drugs for routine use · Diuretics for fluid retention · ACEI or ARB · Beta blockers · Aldosterone antagonists Drugs for use in selected patients · Hydralazine/isosorbide dinitrate · ACEI and ARB · Digoxin In selected patients · CRT · ICD · Revascularization or valvular surgery as appropriate STAGE D Refractory HF THERAPY Goals · Prevent HF symptoms · Prevent further cardiac remodeling Drugs · ACEI or ARB as appropriate · Beta blockers as appropriate In selected patients · ICD · Revascularization or valvular surgery as appropriate e.g., Patients with: · Known structural heart disease and · HF signs and symptoms HFpEF HFrEF THERAPY Goals · Heart healthy lifestyle · Prevent vascular, coronary disease · Prevent LV structural abnormalities Drugs · ACEI or ARB in appropriate patients for vascular disease or DM · Statins as appropriate THERAPY Goals · Control symptoms · Improve HRQOL · Reduce hospital readmissions · Establish patient’s end- of-life goals Options · Advanced care measures · Heart transplant · Chronic inotropes · Temporary or permanent MCS · Experimental surgery or drugs · Palliative care and hospice · ICD deactivation Refractory symptoms of HF at rest, despite GDMT At Risk for Heart Failure Heart Failure e.g., Patients with: · Marked HF symptoms at rest · Recurrent hospitalizations despite GDMT e.g., Patients with: · Previous MI · LV remodeling including LVH and low EF · Asymptomatic valvular disease e.g., Patients with: · HTN · Atherosclerotic disease · DM · Obesity · Metabolic syndrome or Patients · Using cardiotoxins · With family history of cardiomyopathy Development of symptoms of HF Structural heart disease Yancy, C. Jessup M, Bozkurt B. et al. JACC 2013
  19. 19. ACE Inhibitors • Improve survival in patients with all severities of heart failure. • Considered the mainstay of therapy • Begin therapy low and titrate up as possible: • Enalapril – 2.5 mg po BID • Captopril – 6.25 mg poTID • Lisinopril – 5 mg po QDaily • Tolerability can be an issue SOLVD NEJM 1991;325:293-302. SOLVD Investigators NEJM 1992;327:685-691 V-HeFT II NEJM 1991;325:303-310 CONSENSUS NEJM 1987;316:1429-1435 HOPE NEJM 2000;342:145-153 SAVE NEJM 1992;327:669-677
  20. 20. Drug Initial Daily Dose(s) Maximum Doses(s) Mean Doses Achieved in Clinical Trials ACE Inhibitors Captopril 6.25 mg 3 times 50 mg 3 times 122.7 mg/d Enalapril 2.5 mg twice 10 to 20 mg twice 16.6 mg/d Fosinopril 5 to 10 mg once 40 mg once --------- Lisinopril 2.5 to 5 mg once 20 to 40 mg once 32.5 to 35.0 mg/d Perindopril 2 mg once 8 to 16 mg once --------- Quinapril 5 mg twice 20 mg twice --------- Ramipril 1.25 to 2.5 mg once 10 mg once --------- Trandolapril 1 mg once 4 mg once --------- 2013 ACCF/AHA Guideline for the Management of Heart Failure Which ACE I; How Much?
  21. 21. ARB therapy • Considered by some the starting point or equivalent • Somewhat better tolerated as compared to ACE-I therapy • Can have cross-intolerance issues ELITE II (Lancet 2000;355:1582-1587) RESOLVD (Circulation 1999;100:1056-1064) ValHeFT (NEJM 2001;345:1667-1675) CHARM - Overall (Lancet 2003;362:759-766)
  22. 22. ACC/AHA Guidelines 2013 Drug Initial Daily Dose(s) Maximum Doses(s) Mean Doses Achieved in Clinical Trials ARBs Candesartan 4-8 mg qd 32 mg qd 24mg/d Losartan 25-50 mg qd 50 to 100 mg qd 129 mg/d Valsartan 20-40 mg BID 160 mg bid 254 mg/d Which ARB; How Much?
  23. 23. Beta Blocker therapy • Certain Beta blockers (carvedilol, metoprolol, bisoprolol) can improve overall and event free survival in NYHA class II to III HF, probably in class IV. • Require some “selling” as effects are noticed by patients • Slow, careful titration • Contraindicated: • Heart rate <60 bpm • Symptomatic bradycardia • Signs of peripheral hypoperfusion • COPD, asthma • PR interval > 0.24 sec, 2nd or 3rd degree block CIBIS II (Lancet 1999;353:9-13) MERIT-HF (Lancet 1999;353:2001-2007) US Carvedilol Heart Failure Trial (NEJM 1996;334:1349-1355) CAPRICORN (Lancet 2001;357:1385-1390) COMET (Lancet 2003;362:7-13)
  24. 24. Drug Initial Daily Dose(s) Maximum Doses(s) Mean Doses Achieved in Clinical Trials Beta Blockers Bisoprolol 1.25 mg qd 10 mg qd 8.6 mg/d Carvedilol 3.125 mg bid 50 mg bid 37 mg/d Carvedilol CR 10 mg qd 80 mg qd --------- Metoprolol succinate extended release (metoprolol CR/XL) 12.5 - 25 mg qd 200 mg qd 159 mg/d 2013 ACCF/AHA Guideline for the Management of Heart Failure Which Beta Blocker; How Much?
  25. 25. Hydralazine ISDN V-HeFT I (NEJM 1986;314:1547-1552) V-HeFT II (NEJM 1991;325:303-310) A-HeFT (NEJM 2004;351:2049-2057)
  26. 26. Dose and Administration V-HeFT I (NEJM 1986;314:1547-1552) V-HeFT II (NEJM 1991;325:303-310) A-HeFT (NEJM 2004;351:2049-2057) BiDil Remember: This is on top of effective ACE/Beta-Blocker therapy
  27. 27. Diuretics •Loop diuretics • Furosemide, Bumetanide, Torsemide • For Fluid control, and to help relieve symptoms in all stages • Tolerance – may be aided with addition of metolazone • Compensatory Reset •Potassium-sparing diuretics • Spironolactone, Eplerenone • Help enhance diuresis • Maintain potassium • Shown to improve survival in CHF
  28. 28. RALES (NEJM 1999;341:709-717) EPHESUS (NEJM 2003;348:1309-1321
  29. 29. Drug Initial Daily Dose(s) Maximum Doses(s) Mean Doses Achieved in Clinical Trials Aldosterone Antagonists Spironolactone 12.5 to 25 mg qd 25 mg qd 26 mg/d Eplerenone 25 mg qd 50 mg qd 42.6 mg/d • Eplerenone is a more specific aldosterone receptor antagonist; it can be used if spironolactone causes gynecomastia or breast pain. • It causes the same effects on potassium and renal function as spironolactone. Aldosterone Antagonists
  30. 30. Medical Therapy for Stage C HFrEF: Magnitude of Benefit in RCTs RR ↓ Mortality NNT to ↓ mortality (standardized 36 months) RR ↓ HF Hospital. ACE I / ARB 17% 26 31% Beta-Blockers 34% 9 41% Aldosterone Antagonists 30% 6 35% Nitrates/Hydralazine 43% 7 33%
  31. 31. Neprilysin as a Therapeutic Target Inactive fragments Neprilysin Natriuretic peptides Adrenomedullin Bradykinin Substance P (angiotensin II) • Neprilysin breaks down endogenous vasoactive peptides, including the natriuretic peptides • Inhibition of neprilysin potentiates the action of those peptides • Because angiotensin II is also a substrate for neprilysin, neprilysin inhibitors must be co-administered with a RAAS blocker • The combination of a neprilysin inhibitor and an ACEI is associated with unacceptably high rates of angioedema Corti R et al. Circulation. 2001;104:1856-1862. Sacubitril/Valsartan (LCZ696): Angiotensin Receptor–Neprilysin Inhibitor (ARNI)
  32. 32. Neprilysin
  33. 33. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure John J.V. McMurray, M.D., Milton Packer, M.D., Akshay S. Desai, M.D., M.P.H., Jianjian Gong, Ph.D., Martin P. Lefkowitz, M.D., Adel R. Rizkala, Pharm.D., Jean L. Rouleau, M.D., Victor C. Shi, M.D., Scott D. Solomon, M.D., Karl Swedberg, M.D., Ph.D., Michael R. Zile, M.D., for the PARADIGM-HF Investigators and Committees NEJM Volume 371(11):993-1004 September 11, 2014
  34. 34. 1. McMurray JJ et al. N Engl J Med. 2014;371:993-1004 PARADIGM-HF: CV Death or HF Hospitalization (Primary Endpoint)
  35. 35. Sacubitril/Valsartan (ARNI) • Administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB • If switching from an ACE inhibitor a washout period of 36 hours is required • The starting dose of is 49/51 mg (sacubitril/valsartan) twice-daily doubled after 2 to 4 weeks to the target maintenance dose of 97/103 mg (sacubitril/valsartan) twice-daily
  36. 36. Sacubitril/Valsartan • Angioedema risk is low but higher in black patients • Hypotension (18%), hyperkalemia (12%), renal impairment (5%) were the most common side effects observed in the Paradigm study • Interactions similar to ACE inhibitors – NSAIDS – Lithium – Potassium and diuretics • Some concerns Alzheimer's potential • Consider spacing from other vasoactive agents, metoprolol better tolerated vs. carvedilol?
  37. 37. Medical Therapy for Stage C HFrEF: Magnitude of Benefit in RCTs ↓ Mortality NNT to ↓ mortality (standardized 36 months) ↓ HF Hospital. ACE I / ARB 17% 26 31% Beta-Blockers 34% 9 41% Aldosterone Antagonists 30% 6 35% Nitrates/Hydralazine 43% 7 33% ARNI +15% 21 21%
  38. 38. Results of random effect network meta-analysis for all-cause mortality: hazard ratios for intervention versus placebo for all- cause mortality and 95% credible intervals. Heather Burnett et al. Circ Heart Fail. 2017;10:e003529
  39. 39. If current of Funny current
  40. 40. Ivabradine • The funny current drives the rate of diastolic depolarization ultimately the automaticity of the sinus node • As the funny current controls the rate of the sinus node activity, it determines the heart rate • Ivabradine selectively blocks the HCN channels activity reducing persistent elevated heart rate seen in many HF patients
  41. 41. 0 10 20 30 40 50 60 0 1 2 3 incidenceofprimarycompostieendpoint(%) Time (years) Ivabradine, Less severe Ivabradine, Severe Placebo, Less severe Placebo, Severe Efficacy of ivabradine in patients according to heart failure severity www.shift-study.com Borer JS, et al. Am J Cardiol. 2013. 2014;113(3):497-503
  42. 42. Efficacy of ivabradine in patients with heart failure www.shift-study.com Lancet Volume 376, No. 9744, p875–885, 11 September 2010 Borer JS, et al. Am J Cardiol. 2013. 2014;113(3):497-503
  43. 43. Efficacy of ivabradine in patients with heart failure www.shift-study.com Lancet Volume 376, No. 9744, p875–885, 11 September 2010 Borer JS, et al. Am J Cardiol. 2013. 2014;113(3):497-503 • SHIFT showed • Heart-rate reduction improves clinical outcomes and plays an important role in the pathophysiology of this disorder • Raised heart rate (≥70 bpm) is known to be a risk factor in patients with stable coronary artery disease and left ventricular dysfunction • Ivabradine decreased incidence of hospitalization and incidence of heart failure related death • SHIFT supports lowering HR to 60 for optimal outcome • Criticism – optimized beta-blocker use at baseline in the study population
  44. 44. Efficacy of ivabradine in patients with heart failure • Indication HFREF with HR>60 after maximization of beta-blocker therapy or in patients with beta-blocker intolerance • Not used in patients with baseline HR <60, those with heart blocks, patients with pacemaker, BP <90/60, ADHF, advanced liver disease • Main Efficacy measure HR between 50-60
  45. 45. HFrEF: Medications ↓ Symptoms ↓ Hospitalizations ↓ Mortality Diuretics √ √ (?) ? ACE I /ARBs √ √ √ Beta-Blockers √ √ √ Aldosterone Antagonists √ √ √ Digitalis √ √ X Nitrates/Hydralazine √ √ √ ARNI √ √ √ Ivabradine √ √ X
  46. 46. Treatment of heart failure Tool for the Provider NYHA I NYHA II NYHA III NYHA IV Ischemic etiology Nonischemic etiology ACEI/ARB + BB + ASA ACEI/ARB ACEI/ARB + BB + ASA + spironolacton + diuretics ACEI/ARB + BB + diuretics Affects morbidity/ mortality Affects “only“ symptoms of HF ARNI/ACEI/ARB + BB + spironolactone + Ivabradine + diuretics + digoxin Advanced Interventional ARNI/ACEI/ARB + BB + spironolactone + Ivabradine + diuretics + digoxin Program Teaching Tool
  47. 47. Depression & Anxiety in Patients with HF • Moderate-to-Severe depression and anxiety increases mortality in HF • Patients are twice as likely to be seen in the ER if Depression/Anxiety are present • Knowing the patient is key to discovering changes in behavior & attitude • Caregiver reporting must be welcome and should be sought
  48. 48. Within 7-10 days of discharge • Assess Laboratory Findings and Address Issues • Cover Medications with the Patient & Caregiver Frequently • Talk About Smoking Cessation • Discuss Vaccination Importance and Record Maintenance • Talk About Diet • Talk About Exercise Goals • Discuss the importance of recording weight • Consider Provider Directed Diuretic Protocol
  49. 49. Subtitle Acute-Chronic-Acute-Chronic Interrupting the Revolving Door of Chronic Heart Failure

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