Heart Failure: What s s New? Disclosures Speaker honorarium: Astra Zeneca The 10 th Annual Contemporary Cardiovascular Therapy Fall Symposium September 18 & 19 th, 2010 Saskatoon, SK Sheri L. Koshman BScPharm, PharmD, ACPR Assistant Professor, Division of Cardiology, University of Alberta Clinical Pharmacotherapy Practitioner, Alberta Health Services, Pharmacy Services sheri.koshman@ualberta.ca Objectives By the end of this presentation the participants should be able to: Define and describe the stages of heart failure (HF) Characterize the utility of B-type B natriuretic peptide in HF Understand the approach to utilization of beta-blocker blocker in acutely decompensated HF Describe the current utility of combination ACEi and ARB treatment in HF Outline the role of fish oils in treatment of HF Highlight the recent clinical trials investigating the role of statins in established HF Describe the role of the pharmacist in the care of patients with HF HF Prevalence in Canada 4 Chow C-M et al. Can J Cardiol 2005;21(14):1265-71. Heart Failure Mortality Canada s average annual in-hospital mortality rate is: 9.5 deaths/100 hospitalized patients >65 years of age 12.5 deaths/100 hospitalized patients >75 years of age Number of CHF Deaths (actual and projected) in Canada, 1980-2025 HF patients have a poor prognosis, with an average 1-year mortality rate of 33% 5 Lee DS et al. Can J Cardiol 2004;20(6):599-607. 6 Heart and Stroke Foundation of Canada.
Number of Hospitalizations for CHF (actual and projected) in Canada 1980-2025 HF Readmissions Hospital readmission rates are high, and mainly due to recurrent heart failure 7 Heart and Stroke Foundation of Canada. 8 Lee DS et al. Can J Cardiol 2004;20(6):599-607. What is heart failure (HF)? Terminology Complex clinical syndrome Decrease cardiac output Any structural or functional disorder that impairs ventricular (right or left) filling (diastolic) or ejection (systolic) of blood Congestive Heart Failure Classification of HF NYHA Class I II III IV Symptoms No symptoms Symptoms with ordinary activity Symptoms with less than ordinary activity Symptoms at rest Functional capacity Inter-rater rater variability Difficult to detect small changes Can move up and down classes AT RISK OF HEART FAILURE HEART FAILURE N Engl J Med 2003;348(20):2007-17
14 B-type natriuretic peptide (BNP) Elevated BNP Predictive of HF BNP is secreted by ventricular myocytes in response to excessive stretch BNP Trial ROC curves for BNP predicting diagnosis of CHF in patients with or without CHF history Strunk A et al. Am J Med 2006;119:69:e1-11. 15 16 NT-proBNP Complements Clinical Judgment BNP and NT-proBNP In HF Cut Points Rule out for HF Diagnosis Rule in Moe GW et al. Circulation 2007;115(24):3103-10. Arnold JMO, Howlett JG, et al. Can J Cardiol 2007;23(1):21-45. 18 BNP Factors affecting BNP: any condition resulting in myocardial stretch may levels acute PE, ACS, primary pulmonary hypertension, renal failure, cor pulmonale, atrial fibrillation Age (NT-proBNP) Obesity (NT-proBNP and BNP): lower cutoff values Future role of BNP: Risk stratification prognosis intensity of treatment Titration and tailoring of medications BNP/NT-proBNP in Heart Failure Recommendations BNP or NT-proBNP should be measured to help confirm or rule out a diagnosis of HF in the acute or ambulatory care setting in patients in whom the clinical diagnosis is in doubt (Class I, Level A) Measurement may also be considered in patients with known HF for prognostic stratification (Class IIa, Level A) Sequential measurement of BNP/NT-proBNP levels may be considered to guide therapy in HF patients (Class IIb, Level B) Arnold JMO, Howlett JG, et al. Can J Cardiol 2007;23(1):21-45.
Beta-blocker in acute HF decompensation Can J Cardiol 2006;22(1):23-45. In patients with HF admitted to hospital with AHF, what strategy should be used to manage b-b blocker therapy? 1) continue b-blockerb blocker 2) decrease b-blocker b blocker dose 3) discontinue b-blockerb blocker 4) what s s a b-blocker? b blocker? B-CONVINCED: Beta-blocker CONtinuation Vs. Interruption in patients with Congestive heart failure hospitlaized for a decompensation episode Patient population: LVEF < 40%; previously stable of b-blocker b blocker therapy (x 1 mos); hospitalized with AHF Intervention: continuing a b-blockerb blocker Comparator: discontinuing a b-blocker b blocker (for at least 3 days) Outcome: improvement in general well-being and dyspnea in 3d according to a blinded physician Euro Heart J 2009;2186-92 B-CONVINCED: Beta-blocker CONtinuation Vs. Interruption in patients with Congestive heart failure hospitlaized for a decompensation episode Design: open-label, RCT, non-inferiority Outcome: physician blinded questionnaire Follow-up: 3 months Results: n=169 (only 147 analyzed; questionnaires > Day 3 ) Male = 50%; Age = 73 yo; ischemic etiology = 60%; LVEF = 32%; BB < 50% max dose = 52%; ACEI = 65% B-CONVINCED: Beta-blocker CONtinuation Vs. Interruption in patients with Congestive heart failure hospitalized for a decompensation episode Results: Improvements in dyspnea and well being Day 3: 92.8% keep group vs. 92.3% stop group (unilateral 95% CI: -7.6-6.6%) 6.6%) pre-defined limit 12.5%; therefore non-inferior BNP, LOS, re-hosp rate, mortality rate after 3 mos were similar between groups Rates of b-blocker b blocker significantly higher at 3 mos in keep group (90% vs 76%; p<0.05) Euro Heart J 2009;2186-92 Euro Heart J 2009;2186-92
B-CONVINCED: Beta-blocker CONtinuation Vs. Interruption in patients with Congestive heart failure hospitlaized for a decompensation episode Conclusions: Strategy of continuing b-blockers b blockers during an acute decompensation is non-inferior to discontinuation of therapy Continuing the b-blocker b blocker during this period increased use at 3 mos Guidelines now supported by RCT (with limitations) Euro Hear J 2009;2186-92 Heart Failure and Acute Intercurrent Medical Illness Recommendations Continue beta-blockers and ACE-I at their usual dose during acute intercurrent illness (eg, pneumonia, exacerbation of COPD, other systemic infection, etc), unless they are not tolerated (eg, if significant reactive airways disease is present) (Class IIa, Level C) In a life-threatening complication, beta-blockers and ACE-I or ARBs may be discontinued abruptly, but Generally, the dose should be decreased by one-half, and the patient should be reassessed Dose should be uptitrated to the previous well-tolerated dose as soon as safely possible (Class IIa, Level C) Arnold JMO, Howlett JG, et al. Can J Cardiol 2007;23(1):21-45. 26 27 Heart Failure and Acute Intercurrent Medical Illness Recommendations Initiate beta blockers as soon as possible after diagnosis of HF, including during the index hospitalization, provided that the patient is clinically stable. Clinicians should not wait until hospital discharge to start a beta blocker in stabilized patients (Class I, Level B) Continue beta blockers in patients hospitalized with acute HF unless they develop cardiogenic shock, refractory volume overload or symptomatic bradycardia (Class IIa, Level C) ACEi and ARB combination therapy Arnold JMO, Howlett JG, et al. Can J Cardiol 2007;23(1):21-45. Heart Failure: Mortality When to Use ARBs as Add-on Therapy? In patients with persistent HF symptoms, and who are at increased risk of HF hospitalization, despite optimal treatment with ACE inhibitors and beta-blockers (Class I, Level A) Pfeffer MA et al. Lancet 2003;363:759-66. Cohn JN et al. N Engl J Med 2001;345:1667-75. 29 Arnold JMO, Liu P et al. Can J Cardiol 2006;22(1):23-45. Ann Intern Med 2004;141:693-704
Heart Failure: Hospitalizations Heart Failure: ADRs Hyperkalemia RR 4.17 Hypotension RR 1.91 Ann Intern Med 2004;141:693-704 J Card Fail 2008;14:181-8 Heart Failure: ADRs Implications Small additive benefit of add-on therapy in terms of HF hospitalization Renal Dysfunction RR 2.12 Systematic review of ADR indicates significant increase in ADRs Any Side Effect RR 1.27 Needs to balanced benefit with risk of ADR in selected patients J Card Fail 2008;14:181-8 Statins and Fish Oils Statins should be used in ischemic HF because these patients are at high risk of vascular events True False
Beneficial effects of statins in HF: Pleiotrophic effects Clinical effects Background Reduction of MI is the main benefit of statins Low rates of MI in HF Autopsy studies ACS are a common underlying cause of SCD and death from pump failure most common causes of death in HF Deleterious effects of statins in HF: Retrospective studies lower TC is associated with higher mortality in advanced HF cause of mortality or reflection of advanced disease J Am Coll Cardiol 2008;51:415-26 Cardiovasc Research 2006;71:443-54 Background Clinical trials: Retrospective trials decrease in mortality Clinical databases Post-hoc analysis Prospective trials systematically excluded HF patients 2 placebo-controlled controlled RCTs improvement of symptoms small, placebo controlled trials decrease in mortality 2 2 SCD small, RCT of atorvastatin 10mg vs placebo only published in abstract form decrease HF hospitalizations TNT trial small subgroup n=286 J Am Coll Cardiol 2008;51:415-26 Cardiovasc Research 2006;71:443-54 Corona trial Rosuvastatin in Older Patients with Systolic Heart Failure (CORONA) Patient population In elderly patients, >60 yr, with HF (NYHA II-IV, IV, EF < 40%) secondary to CAD (ischemic) Intervention does rosuvastatin 10mg Comparator compared to placebo Outcome decrease death from CV causes, nonfatal MI or nonfatal stroke N Engl J Med 2008; 357:1-14 Corona trial Rosuvastatin in Older Patients with Systolic Heart Failure (CORONA) Design: MC, placebo controlled, RCT Follow-up: median 32.8 mos Results: n = 5011 Male 76%; mean age = 73; LVEF = 31%; ACEi/ARB = 92%; BB = 75%; aldosterone antagonist = 40% LDL 44% (baseline LDL 3.5) & CRP 32% in rosuvastatin group N Engl J Med 2008; 357:1-14 Results OR = 0.92 (0.83-1.02) OR = 0.95 (0.86-1.05) Implications Neutral effect Expected lipid lowering (LDL 44%) RRR expected per mmol/l lowering 12% all cause mortality 19% CV mortality 21% major CV events Expected CRP lowering (Pleiotrophic effects) Dose too low (METEOR 40mg, JUPITER 20mg) Primary outcome: CV death, non-fatal MI, non-fatal stroke Kjekshus J, et al. N Engl J Med 2008; 357:1-14
Implications Study population mean age = 73, multiple co-morbidities moderate-severe HF too late in the progress of disease selection bias too sick to warrant treatment in the first place Low rates of events Sample size =1424; actual = 1424 CV death main driver conservative definition 9.5%, PROSPER = 4%, COMET = 30% MI rates =2.4%, other studies = PROSPER 8%, CHARM 5-7% 5 Implications Optimal background therapy for HF high rates of EBM, limited incremental benefit Follow-up duration too short (2.7 yrs) benefits with statins seen as early as 1 year (1.9-5.2 years, 4.7 years) What about patients with HF that are already on a statin? Patient population In patients, >18 yr, with HF (NYHA II-IV) IV) of any etiology Intervention does rosuvastatin 10mg (2X2 factorial with fish oils) Comparator compared to placebo Outcome decrease time to death / time to death or CV hospitalization Design: MC, placebo controlled, RCT Follow-up up: median 3.9 years Results: n = 4631 Male 78%; mean age = 68, 44% > 70; LVEF = 33%; ischemic = 40%; dilated = 34%; ACEi/ARB = 93%; BB = 62%; aldosterone antagonist = 40% LDL 30% (baseline LDL 3.16) & CRP 17% in rosuvastatin group Results HR = 1 (0.89-1.12) HR = 1.01 (0.91-1.11) All cause mortality All cause mortality / CV hosp Implications Compared to CORONA Only 40% ischemic etiology 37% vs. 63% NYHA III-IV IV age 68 vs 73 yo outcomes: CV death/hospitalization vs. MACE Likely not harmful (no difference in ADRs), but limited benefit Little role in non-ischemia HF
49 Statin therapy in HF Recommendation Statin therapy may be considered for patients with systolic HF of ischemic etiology in accordance with primary and secondary prevention guidelines (Class 2A, Level B) Practical Tips Routine statin therapy is unlikely to provide clinical benefit for patients with active HF due to nonischemic causes and in the absence of very high risk of vascular events The decision to treat should be made on the basis of existing prevention guidelines, as current data doesn t reflect a strong recommendation It is reasonable to consider statin withdrawal in patients with refractory HF, or where reduction in polypharmacy or palliative care is an overriding concern Howlett JG, McKelvie RS, Arnold JMO et al. Can J Cardiol 2009;25(2):85-105. Fish Oils (ω-33 PUFA) Major Classes of Fatty Acids Background Epidemiological date indicates that omega-3 3 polyunsaturated fatty acids (ω-3( PUFA) are associated with in CV events and HF Post-MI RCTs indicate a in CV events sudden cardiac death (SCD) and worsening LV function SCD is a common mode of death in HF J Am Coll Cardiol 2009;54:585-94 J Am Coll Cardiol 2009;54:585-94 Patient population In patients, > 18 yo, with HF (NYHA II-IV) IV) of any etiology Intervention does 1g ω-3 3 PUFA daily (1.2:1; EPA:DHA, 850-882mg) Comparator compared to placebo Outcome decrease time to death/ time to death or CV hospitalization Design: MC, placebo controlled, RCT Follow-up up: median 3.9 years Results: n = 6975 Male 78%; mean age = 67, 42% > 70; LVEF = 33%; ischemic = 50%; dilated = 30%; LVEF > 40 = 10%; ACEi/ARB = 93%; BB = 65%; aldosterone antagonist = 40% EPA = eicosapentaenoic acid DHA = docosahexaenoic acid
HR = 0.91(0.83-0.99) ARR =1.8%; NNT = 56 Results HR = 0.92(0.85-0.99) ARR =2.3%; NNT = 44 Results Discontinuation rate = 30% ADRs = 3% in both arms mainly GI; similar in both groups no difference in bleeding between arms Anticoagulants = 30% ASA = 48% All cause mortality All cause mortality / CV hosp 58 Implications Small benefit, but incremental over baseline HF treatment in all cause mortality benefits realized after 2 years Omega-3 Polyunsaturated Fatty Acid (or Fish Oil) Supplementation Recommendation Low-dose omega-3 polyunsaturated fatty acid (n-3 PUFA) therapy (1 g/day) may be considered for reduction in morbidity and mortality in patients with mild-to-moderate HF (Class 2a, Level B) Practical Tips Since most data available for n-3 PUFAs have been reported in patients with HF and an ejection fraction of <40%, extrapolation of these results to patients with HF and preserved ejection fraction should be made with caution Howlett JG, McKelvie RS, Arnold JMO et al. Can J Cardiol 2009;25(2):85-105. 2 oily fish meals per week = 500mg EPA/DHA per day **Methyl mercury: higher in swordfish, tile fish, king mackerel and shark; water soluble and protein bound therefore negligible amounts in oil (more muscle) J Am Coll Cardiol 2009;54:585-94 J Am Coll Cardiol 2009;54:585-94
Role of the pharmacist Multidisciplinary HF Management Meta-Analysis Duration of interventions in the pooled studies ranged from one visit to 30 months. 62 McAlister FA et al. J Am Coll Cardiol 2004;44:810-9. Objective: To determine if proactive pharmacist involvement in HF management improves patients health-related outcomes Primary outcomes: mortality total hospitalizations HF hospitalizations Inclusion criteria: RCTs HF patients proactive pharmacist involvement in the care of patients with HF pharmacist directed, pharmacist added to team, other authors were contact for clarification and verification All cause hospitalizations Results: 12 articles included Pharmacist directed (n=7) Pharmacist collaborative care (n=5) Interventions: HF medication recommendations HF medication and disease education (verbal and written) Self-monitoring Liaison with other healthcare providers Adherence assessment and aids Follow-up (telephone and in person) OR 0.71 (0.54-0.94)
HF hospitalization OR 0.69 (0.51-0.94) Clinical heterogeneity pharmacist activities varied between studies likelihood of different co-interventions across studies different patient populations and settings Quality of studies all unblinded only 4 studies used intention-to to-treat treat analysis Implications Questions Pharmacist improve hard outcomes in patients with HF The most benefit is seen when adding a pharmacists to a team Current (2010 CCS) guidelines reflect this evidence