10/4/2016 Target Dose vs Highest Tolerated Dose: Beta- Blocker - PDF document

10/4/2016 Target Dose vs Highest Tolerated Dose: Beta- Blocker Therapy in Heart Failure in the Elderly JASMINE PETERSON, PHARMD PGY-2 AMBULATORY -CARE RESIDENT COMMUNITYCARE CLINIC UNIVERSITY OF TEXAS COLLEGE OF PHARMACY AT AUSTIN OCTOBER 7, 2016 OBJECTIVES  By the end of this presentation attendees will be able to:  Understand the epidemiology and pathophysiology of heart failure  Describe the challenges of managing heart failure in elderly patients  Summarize the literature regarding the controversy behind achieving target doses of beta blockers in elderly heart failure patients 2 DEFINITION OF ELDERLY  According to the World Health Organization (WHO), most developed countries have accepted the chronological age of ≥65 years as a definition of “elderly” or older persons  A consensus definition does not exist  May vary in underdeveloped countries 3 http://www.who.int/healthinfo/survey/ageingdefnolder/en/ 1

10/4/2016 HEART FAILURE BACKGROUND 4 HEART FAILURE Heart failure (HF) is defined as a complex clinical syndrome caused by structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood Figure 1. 5 DEFINITIONS HF reduced ejection fraction HF preserved ejection (HFrEF) fraction (HFpEF) Systolic dysfunction Diastolic dysfunction Secondary to impaired ventricular Secondary to dilated ventricles filling Left ventricular ejection fraction LVEF ≥50% (LVEF) ≤40% Randomized controlled trials have Currently, efficacious therapies have mainly enrolled these patients not shown proven mortality benefit 6 Circulation. 2013;128:e240-e327 2

10/4/2016 CLASSIFICATIONS Table 1. ACCF/AHA NYHA A At high risk for HF but without None structural heart disease or symptoms of HF B Structural heart disease but without I No limitation on physical activity signs and symptoms of HF C Structural heart disease but with I No limitation on physical activity prior or current symptoms of HF II Slight limitation of physical activity III Marked limitation of physical activity IV Unable to carry on any physical activity without symptoms of HF D Refractory HF requiring specialized IV Unable to carry on any physical activity 7 interventions without symptoms of HF American Heart Association (AHA); American College of Cardiology Foundation (ACCF) ; New York Heart Association(NYHA) Circulation. 2013;128:e240-e327 EPIDEMIOLOGY Prevalence • Lifetime risk of developing HF is 20% for patients ≥40yo • >650,000 new HF cases each year Mortality • 50% within 5 years of diagnosis Hospitalizations • 75% occur in patients >65yo • Leading cause of readmissions • >$30 billion for HF care annually 8 Circulation. 2013;128:e240-e327 Christine K. Cassel et. al., ed. 2003. Geriatric Medicine: An Evidence Based Approach - 4th Ed PREVALENCE OF HF IN THE ELDERLY Figure 2. Prevalence of HF by sex and age (National Health and Nutrition Examination  Factors contributing to the rise and Survey 2009-2012) incidence of HF 16  Age-related cardiovascular changes 14  High prevalence of cardiovascular 12 Percentage 10 disease 8  Improved therapies for coronary Male 6 Female heart disease 4 2 0 20-39 40-59 60-79 80+ Age (years) 9 Darish Mozaffarian et al. Circulation.2016;133:e133:e38-e360. 3

10/4/2016 PATHOPHYSIOLOGY Figure 3. Vaso constriction SNS ↑Norepinephrine, adrenaline, BP , HR, contractility, etc. Vasoconstriction Myocardial Injury RAAS ↑BP, sympathetic tone, aldosterone, hypertrophy, fibrosis, etc. Vasodilation NPS ↓BP, hypertrophy, fibrosis, sympathetic tone, etc. Natriuretic Peptide system (NPS) 10 Sympathetic Nervous System (SNS) Renin Angiotensin Aldosterone System (RAAS) ClinTher. 2015;37:2199 – 2205 CLINICAL PRESENTATION/RISK FACTORS • Dyspnea • Fatigue Primary Symptoms • Edema • Exercise intolerance • Coronary artery disease (CAD) • Valvular heart disease • Uncontrolled chronic disease (i.e. Hypertension) Risk Factors • Cardiomyopathy • Myocarditis • Pericardial disease 11 Circulation. 2013;128:e240-e327 Am J Geriatr Pharmacother. 2009;7:233 – 249. CHALLENGES OF MANAGING HF IN THE ELDERLY Physiological age-related changes • Influence drug pharmacokinetics and dynamics More complex comorbidities • Higher risk for drug-related side effects • Polypharmacy Social issues • Limited access to caregivers and specialists • Cognitive impairment • Financial problems affect therapy adherence 12 Am J Geriatr Pharmacother. 2009;7:233 – 249. 4

10/4/2016 TREATMENT: NON-PHARMACOLOGIC AND PHARMACOLOGIC 2013 ACCF/AHA GUIDELINE FOR THE MANAGEMENT OF HF 2016 ACC/AHA/HFSA FOCUSED UPDATE ON NEW PHARMACOLOGICAL THERAPY FOR HF: AN UPDATE OF THE 2013 ACCF/AHA GUIDELINE 13 NON-PHARMACOLOGIC RECOMMENDATIONS  Patient education  Restrict sodium intake (1.5- 2 grams/day)  Weight control  Manage/control underlying causes  Intensive follow-up  Smoking cessation  Restrict alcohol 14 Am J Geriatr Pharmacother. 2009;7:233 – 249 PHARMACOLOGIC RECOMMENDATIONS Table 3. Stage Goals Treatment Recommendations Stage A Prevent structural heart damage and ACEI/ARB in patients with vascular promote heart healthy lifestyle disease or DM Stage B Prevent HF symptoms and further cardiac ACEI/ARB and beta blockers as remodeling appropriate Stage C Control symptoms, prevent morbidity and Diuretics, ACEI/ARB, ARNI, beta mortality, and slow progression of worsening blockers , aldosterone antagonists, cardiac function hydralazine/isosorbide dinitrate, digoxin, ivabradine Stage D Control symptoms, improve quality of life, Advanced care measures, heart reduce hospital admissions, establish end-of- transplant, chronic inotropes, implantable life goals cardiac device, palliative care Angiotensin-converting-enzyme inhibitor (ACEI), Angiotensin receptor blocker (ARB) , Angiotensin Receptor Neprilysin Inhibitor (ARNI) 15 5

10/4/2016 BETA BLOCKERS (BBs) BACKGROUND AND ROLE IN HF 16 PROPOSED MECHANISM OF ACTION/BENEFICIAL EFFECTS Figure 4. Beta Blockers Myocardial Injury 17 ClinTher. 2015;37:2199 – 2205 ROLE OF BETA BLOCKERS IN HF  2013 ACCF/AHA HF guidelines states:  “Use of 1 of the 3 beta blockers proven to reduce mortality (i.e. bisoprolol, carvedilol, and sustained-release metoprolol succinate) is recommended for all patients with current or prior symptoms of HFrEF , unless contraindicated, to reduce morbidity and mortality.”  Class I, Level of evidence A  “Clinicians should make every effort to achieve the target doses of the beta blockers shown to be effective in major clinical trials.” 18 6

10/4/2016 EVIDENCE SUPPORTING BETA BLOCKER RECOMMENDATIONS Table 4. Major Placebo- Controlled Trials of BBs Supporting HF Guideline Recommendations Drug Trial Mean N Patient Mean Target % Achieved Mortality/ follow-up Population age dose Target dose Morbidity (mo) (yo) (RRR) Metoprolol MERIT-HF 12 3991 NYHA ll-lV; 64 200 mg daily 64% ↓ 34%/ ↓ 18% XL (1999) LVEF <40% Bisoprolol* CIBIS-II 15.6 2647 NYHA class III- 61 10 mg daily 48% ↓ 34%/ ↓ 20% (1999) IV; LVEF <35% Carvedilol COPERNICUS 10.4 2289 NYHA class lV; 63 25 mg BID 65% ↓ 35%/ ↓ 20% (2002) LVEF <25% CIBIS-II (Cardiac Insufficiency Bisoprolol Study II), MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure), COPERICUS (Carvedilol Prospective Randomized Cumulative Survival) * Not approved in the US RRR= Relative Risk Reduction 19 BACKGROUND: BETA BLOCKERS IN THE ELDERLY 20 Am J Cardiol 2005;95:896 – 898 RESULTS Figure 5. Elderly Non-Elderly 21 Am J Cardiol 2005;95:896 – 898 7

10/4/2016 BETA BLOCKER CLINICAL TRIALS INVESTIGATED Table 5. BB Clinical Trials Included in Meta-analysis BB Trial Mean N Patient Mean age Inclusion % ≥70yo Mortality/ follow-up Population (yo) Criteria Morbidity (mo) (Age, yo) (RRR) Metoprolol XL MERIT -HF (1999) 12 3991 NYHA ll-lV; 64 40-80 31% ↓ 34%/ ↓ 18% LVEF <40% Bisoprolol* CIBIS-II 15.6 2647 NYHA class III- 61 18-80 20% ↓ 34%/ ↓ 20% (1999) IV; LVEF <35% Carvedilol COPERNICUS 10.4 2289 NYHA class lV; 63 ≥18 NR ↓ 35%/ ↓ 20% (2002) LVEF <25% Carvedilol Carvedilol U.S. Trials 6.5 1094 NYHA ll-lV; 59 ≥18 NR ↓ 65%/ ↓ 27% (1996) LVEF <35% Bucindolol* BEST (2001) 24 2708 NYHA llI-lV; 60 >18 28% NS/ ↓ 8% LVEF <35% * Not approved in the US ,NS= not significant ;NR= Not reported, BEST (Beta-Blocker Evaluation of Survival Trial) 22 Am J Cardiol 2005;95:896 – 898 CLINICAL QUESTION Highest tolerated Target dose dose Is achieving target doses of beta blockers in elderly HF patients associated with better clinical outcomes? 23 EVIDENCE EVALUATING THE EFFECT OF BETA BLOCKERS ON CLINICAL OUTCOMES IN ELDERLY HF PATIENTS 24 8

10/4/2016 THE EFFECTS OF BETA-BLOCKERS ON MORBIDITY AND MORTALITY IN A POPULATION-BASED COHORT OF 11,942 ELDERLY PATIENTS WITH HEART FAILURE SIN D., MCALISTER F., ET AL. AM J MED. 2002;113:650 – 656 25 SIN 2002  Aim  Evaluate the associations between BBs and outcomes in older HF patients  Design  Retrospective cohort study  Inclusion Criteria  All residents of Alberta, Canada ≥ 65yo who had at least 1 hospitalization for HF between 1994 and 1999 26 SIN 2002  Exclusion Criteria  Patients who died during the index hospitalization  Patients who had been hospitalized for HF 2 years before the index hospitalization  Endpoints  All-cause mortality  HF hospitalizations 27 9