Cardiovascular Guideline-Driven Pharmacotherapies: Optimizing Management David Parra, Pharm.D., FCCP, BCPS Clinical Pharmacy Program Manager in Cardiology/Anticoagulation VISN 8 Pharmacy Benefits Management Clinical Associate Professor Department of Experimental and Clinical Pharmacology College of Pharmacy, University of Minnesota
Presenter disclosure information Financial Disclosure: I do not have a financial relationships with any commercial entity which may represent, in perception or reality, a conflict of interest in the context of this presentation The views expressed in this presentation reflect those of the author, and not necessarily those of the Department of Veterans Affairs
Objectives Explain what optimizing management with guideline-driven pharmacotherapy entails Optimize management of guideline-driven pharmacotherapy in the treatment of heart failure with reduced ejection fraction (HFrEF) List 3 general barriers to guideline adherence List 3 general strategies most likely to improve guideline adherence
Cardiovascular Guideline-Driven Pharmacotherapy: Optimizing Management Right Drug Right Patient Right Time Optimal Pharmacotherapy Right Dose
Guideline-Driven Pharmacotherapy: Optimizing Management Focus on Heart failure with reduced ejection fraction Complex pharmacotherapy Many opportunities for improvement We are at risk of out with the old in with the new
Applying ACC/AHA Guideline Classification of Recommendations and Levels of Evidence A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/ efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated.
Optimizing Pharmacotherapy in Heart Failure Starts Well Before Heart Failure Develops Symptomatic Heart Failure: Tip of the Iceberg Post-MI Remodelling Familial/Idiopathic Cardiomyopathy Coronary Artery Disease Other CVD Risk Factors Asymptomatic Left Ventricular Dysfunction Left Ventricular Hypertrophy Diabetes Hypertension Adapted from Gregg. C Fonarow, MD. Heart Failure: Scope of the Problem. Heart Failure University. Los Angeles, CA, Nov 12-14, 2004.
Audience Response Question: Optimizing Management Which of the following has a ACCF/AHA Guidelines Class IIa (level of evidence B) recommendation as follows: Reasonable to use as adjunctive therapy in patients with NYHA class II IV symptoms and HFrEF or HFpEF, unless contraindicated, to reduce mortality and cardiovascular hospitalizations (Level of Evidence B) A. ACE inhibitors B. Aldosterone antagonists C. Beta-blockers D. Omega-3 polyunsaturated fatty acids (PUFA)
HFpEF: Treatment Recommendations Omega-3 polyunsaturated fatty acids (PUFA) IIa B Adapted from Table 21. 2013 ACCF/AHA Guideline for the Management of Heart Failure
Audience Response Question: Optimizing Management Presented with a patient with HFrEF NYHA III optimized on a beta-blocker, ACE inhibitor and spironolactone would you rather? A. Add omega-3 polyunsaturated fatty acids (PUFA) B. Add digoxin
HFrEF: Stage C * Treatment Approach: Prior to April 2015 * Structural heart disease with prior or current signs or symptoms of heart failure Class IIa, LOE B Digoxin PUFA Adapted from 2013 ACCF/AHA Guideline for the Management of Heart Failure
ACCF/AHA HF 2013 Recommendations Digoxin Class IIa, - Digoxin can be beneficial in patients with HFrEF, unless contraindicated, to decrease hospitalizations for HF (Level of Evidence B) Omega-3 polyunsaturated fatty acids (PUFA) Class IIa Reasonable to use as adjunctive therapy in patients with NYHA class II IV symptoms and HFrEF or HFpEF, unless contraindicated, to reduce mortality and cardiovascular hospitalizations (Level of Evidence B)
Omega-3 polyunsaturated fatty acids (PUFA) Trial design: 6,975 patients who had New York Heart Association class II-IV failure heart (irrespective of LVEF) were randomly assigned to receive n-3 PUFA 1 g daily. Median follow-up 3.9 years. GISSI-HF investigators. Lancet 2008; Aug 29
Guideline-Driven Pharmacotherapy: Optimizing Management The eye cannot see what the mind does not know - Anonymous
Guideline-Driven Pharmacotherapy: Optimizing Management Just knowing that guidelines exist will not lead to optimization of pharmacotherapy
Underutilized (selected) Traditional Pharmacotherapy in HFrEF Optimal doses of ACE-Is or ARBs Optimal doses of BB Aldosterone antagonists Hydralazine/isosorbide dinitrate
Magnitude of Benefit Demonstrated in RCTs of HFrEF 2013 ACCF/AHA Guideline for the Management of Heart Failure
Dosing of ACE-Is or ARBs in HFrEF Trials (The Ideal) In clinical trials that were designed to evaluate survival, the dose of the ACE inhibitor was not determined by a patient s therapeutic response but was increased until the predetermined target dose was reached Adapted from 2013 ACCF/AHA Guideline for the Management of Heart Failure
Dosing of ACE-Is or ARBs in HFrEF Trials (The Reality) Comparison of Medical Therapy Dosing in Outpatients Cared for in Cardiology Practices With Heart Failure and Reduced Ejection Fraction With and Without Device Therapy Report From IMPROVE HF Results Medical Treatment Total Cohort (n = 15,381) ACE-I/ARB % patients treated 79.6 ACE-I/ARB % patients with contraindications or intolerance Of eligible patients % on target dose or more 30.7-34.6 Of eligible patients % below target dose 56.6-63.1 Of eligible patients % missing dosing data 4.9-8.8 6.5 Circ Heart Fail. 2010;3:596-605.
ACE-Is in HFrEF: How Important is Dose Titration? ATLAS compared with SOLVD Treatments Reduction in risk Reduction in risk compared of death of death or hospitalization for HF High dose vs. placebo (SOLVD) 16% 26% Low dose vs. placebo (not studied) not known not known High dose vs. low dose (ATLAS) 8% 15% Packer et al. Circulation 1999;100:2312-2318.
ARBs in HFrEF: How Important is Dose Titration? HEAAL Trial design: Patients with heart failure and left ventricular ejection fraction 40% were randomized to high-dose losartan 150 mg daily (n = 1,927) vs. low-dose losartan 50 mg daily (n = 1,919). Median follow-up was 4.7 years. 14 Per 100 patient- years 7 (p = 0.027) 11.1 12.4 (p = 0.025) 6.0 7.0 High-dose losartan Low-dose losartan 0 All-cause mortality or heart failure admission Konstam MA, et al. Lancet 2009;374:1840-8 Heart failure admission
How Important is Dose Titration? Disease State Heart Failure* 1950-1969 1-year mortality (men) 30% 1-year mortality (women) 28% 5-year mortality (men) 70% 5-year mortality (women) 57% 1970-1979 41% 28% 75% 59% Titrate 1980-1989 as 33% Tolerated 27% 65% to Doses 51% 1990-1999 28% 24% 59% 45% All Cancer Achieved in Clinical 38% Trials 37.3% Breast Cancer 14.1% Prostate Cancer 2.4% Colon Cancer 38.6% *All values adjusted for age and reported in patients who survived the initial 30 days after the onset of heart failure (Framingham cohort). Cancer survival rates derived from Surveillance, Epidemiology, and End Results (SEER) program 1973-1998 Levy et al. N Engl J Med 2002;347:1397-1402. Brenner H. Lancet 2002;360:1131-35.
Dosing of Beta-blockers with a proven benefit in HFrEF Trials (The Ideal) Achievement of target doses in these trials ranged from 58.6% in the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial to 64% in the Metoprolol Controlled-Release/Extended-Release Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) Adapted from 2013 ACCF/AHA Guideline for the Management of Heart Failure
Dosing of Beta-blockers in HFrEF Trials (The Reality) Comparison of Medical Therapy Dosing in Outpatients Cared for in Cardiology Practices With Heart Failure and Reduced Ejection Fraction With and Without Device Therapy Report From IMPROVE HF Results Medical Treatment Total Cohort (n = 15,381) B-blocker % patients treated 86 B-blocker % patients with contraindications or intolerance 6.8 Of eligible patients % on target dose or more 15.3-20.4 Of eligible patients % below target dose 69.6-72.3 Of eligible patients % missing dosing data 7.9-13 Circ Heart Fail. 2010;3:596-605.
Beta-blockers in HFrEF: How Important is Dose Titration? No randomized clinical trials comparing high dose vs. low dose COMET trial of carvedilol (target 25mg twice daily) vs. lower dose metoprolol tartrate (50mg twice daily) resulted in lower total mortality with carvedilol Post-hoc analysis of pivotal beta-blocker trials in HFrEF revealed better outcomes with higher doses vs. lower Heart rate predictor of mortality in HFrEF What is the evidence for low dose beta-blocker therapy in HFrEF?
Underutilization of Aldosterone Antagonists in HFrEF Observational analysis of 43,625 patients (Get with the Guidelines Registry) with HF with recent discharge Excluded those with contraindications to therapy Of 12,565 who met ACC/AHA guideline criteria 32.5% received therapy JAMA. 2009;302(15):1658-1665
Underutilization of Aldosterone Antagonists in HFrEF Comparison of Medical Therapy Dosing in Outpatients Cared for in Cardiology Practices With Heart Failure and Reduced Ejection Fraction With and Without Device Therapy Report From IMPROVE HF Results Medical Treatment Total Cohort (n = 15,381) Aldosterone antagonists % patients treated 36.1 Aldosterone antagonists % patients with contraindications or intolerance 17.7 Of eligible patients % on target dose or more 70.1-76.5 Of eligible patients % below target dose 18.3-21.8 Of eligible patients % missing dosing data 5.3-9.6 Circ Heart Fail. 2010;3:596-605.
Hydralazine/ISDN: A-HeFT Trial design: 1,050 black patients who had New York Heart Association class III or IV heart failure with EF< 35% were randomly assigned to receive a fixed dose of isosorbide dinitrate plus hydralazine or placebo in addition to standard therapy for heart failure (target 225mg hydralazine; ISDN 120mg). Median follow-up 10 months. 43 percent reduction in the rate of death from any cause [hazard ratio, 0.57; P=0.01] 33 percent relative reduction in the rate of first hospitalization for heart failure [16.4 percent vs. 22.4 percent, P=0.001] Baseline Medications: Diuretic ~90%; ACE inhibitor or ARB ~85%, Beta-blocker ~75%, Digoxin ~60%; Spironolactone ~40% N Engl J Med 2004; 351(20): 2049-57
Utilization of Hydralazine/ISDN in HFrEF In the Get With The Guidelines Heart Failure registry from April 2008 to March 2012Among 11,185 African American patients eligible for H-ISDN therapy, only 2,500 (22.4%) received H-ISDN J Am Heart Assoc. 2013;2:e000214 doi: 10.1161/JAHA.113.000214
Titration to Optimal Doses: My Patient is on Everything Does it still matter?
Guideline-Driven Pharmacotherapy: Optimizing Management Knowledge that the guidelines exist is insufficient but so is familiarity with the guidelines
Cardiovascular Guideline-Driven Pharmacotherapy: Optimizing Management Right Patient Right Drug Right Time Right Drug Right Dose Right Patient Right Dose Right Time Optimal Pharmacotherapy
Guideline-Driven Pharmacotherapy: Barriers to Optimizing Management (Guideline Adherence) Cabana et al. JAMA 1999;282:1458-1465.
Guideline-Driven Pharmacotherapy: Barriers to Optimizing Management (Guideline Adherence) Different guidelines can have different barriers Within a guideline, barriers can differ between recommendations Barriers can change over time (e.g. cost, awareness) Cabana et al. JAMA 1999;282:1458-1465.
Interventions to Improve Adherence to Cardiovascular Disease Guidelines Dissemination of guidelines alone has little to no effect on practice Numerous studies conducted (mostly on physicians), but overall impact on guideline adherence and impact is unclear Strategies that demonstrated the strongest benefit were (in order) organizational change, patient education, provider education, and provider reminder systems Audit and feedback as well as patient self-management showed differing results or small advantages Fam Pract. 2014;31(3):247 66. BMC Fam Pract. 2015;16(147).
Organizational Change to Improve Adherence to Cardiovascular Disease Guidelines Strategies for guideline implementation via organizational change included Improved collaboration with pharmacists, medically supervised nurses, prevention coordinators or hospital specialists Meta-analysis based on 14 trials with 32,465 patients had an overall OR of 1.96 (95% CI 1.40 to 2.75) in favor of organizational change over usual care Fam Pract. 2014;31(3):247 66.
Cardiovascular Team-Based Care Brush JE Jr, Handberg EM, Biga C, Birtcher KK, Bove AA, Casale PN, Clark MG, Garson A Jr, Hines JL, Linderbaum JA, Rodgers GP, Shor RA, Thourani VH, Wyman JF. 2015 ACC health policy statement on cardiovascular team-based care and the role of advanced practice providers. J Am Coll Cardiol 2015;65:2118 36.
Summary Optimizing management with guideline-driven pharmacotherapy entails the right drug, right patient, right dose, and right time Underutilization and under dosing of proven pharmacotherapy is problematic in HFrEF Barriers to guideline adherence are complex and multi-factorial Organizational change, patient education, and provider education appear to have the greatest impact on guideline adherence