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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
Cardiovascular Guideline-Driven
Pharmacotherapies:
Optimizing Management
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 Time
Right Dose
Right Patient
Optimal Pharmacotherapy
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.
HypertensionHypertensionHypertensionHypertension
Left VentricularLeft VentricularLeft VentricularLeft Ventricular
HypertrophyHypertrophyHypertrophyHypertrophy
Familial/IdiopathicFamilial/IdiopathicFamilial/IdiopathicFamilial/Idiopathic
CardiomyopathyCardiomyopathyCardiomyopathyCardiomyopathy
PostPostPostPost----MIMIMIMI
RemodellingRemodellingRemodellingRemodelling
Symptomatic Heart Symptomatic Heart Symptomatic Heart Symptomatic Heart Failure: Tip of the IcebergFailure: Tip of the IcebergFailure: Tip of the IcebergFailure: Tip of the Iceberg
DiabetesDiabetesDiabetesDiabetes
AsymptomaticAsymptomaticAsymptomaticAsymptomatic
Left Ventricular Left Ventricular Left Ventricular Left Ventricular
DysfunctionDysfunctionDysfunctionDysfunction
Coronary Coronary Coronary Coronary Artery DiseaseArtery DiseaseArtery DiseaseArtery Disease
Other CVD Risk FactorsOther CVD Risk FactorsOther CVD Risk FactorsOther CVD Risk Factors
Optimizing Pharmacotherapy in Heart Failure
Starts Well Before Heart Failure Develops
Adapted from Gregg. C Fonarow, MD. Heart Failure: Scope of the Problem. Heart Failure University. Los Angeles, CA, Nov 12-14, 2004.
HFpEF: Treatment Recommendations
Adapted from Table 21. 2013 ACCF/AHA Guideline for the Management of Heart Failure
Omega-3 polyunsaturated fatty acids (PUFA)IIa B
HFrEF: Stage C* Treatment Approach:
Prior to April 2015
Adapted from 2013 ACCF/AHA Guideline for the Management of Heart Failure
*Structural heart disease with prior or current signs or symptoms of heart failure
Class IIa, LOE BClass IIa, LOE BClass IIa, LOE BClass IIa, LOE B
Digoxin
PUFA
ACCF/AHA HF 2013 Recommendations
• Digoxin Class Class Class Class IIaIIaIIaIIa, - Digoxin can be beneficial in patients with HFrEF, unless contraindicated,
to decrease hospitalizations for HF (Level of Evidence BLevel of Evidence BLevel of Evidence BLevel of Evidence B)
• Omega-3 polyunsaturated fatty acids (PUFA) Class IIaClass IIaClass IIaClass 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 BLevel of Evidence BLevel of Evidence BLevel of Evidence B)
Omega-3 polyunsaturated fatty acids (PUFA)
GISSI-HF investigators. Lancet 2008; Aug 29
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.
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
Circ Heart Fail. 2010;3:596-605.
Medical Treatment Total Cohort (n = 15,381)
ACE-I/ARB % patients treated 79.6
ACE-I/ARB % patients with contraindications or intolerance
6.5
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
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.
11.1
6.0
12.4
7.0
0
7
14
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.
Konstam MA, et al. Lancet 2009;374:1840-8
(p = 0.027)(p = 0.027)(p = 0.027)(p = 0.027)
(p = 0.025)(p = 0.025)(p = 0.025)(p = 0.025)HighHighHighHigh----dose dose dose dose
losartanlosartanlosartanlosartan
LowLowLowLow----dose dose dose dose
losartanlosartanlosartanlosartan
AllAllAllAll----cause mortality or cause mortality or cause mortality or cause mortality or
heart failure admissionheart failure admissionheart failure admissionheart failure admission
Heart failure Heart failure Heart failure Heart failure
admissionadmissionadmissionadmission
Per 100 patient
Per 100 patient
Per 100 patient
Per 100 patient -- --
years
years
years
years
Disease State
1-year mortality (men)
1-year mortality (women)
5-year mortality (men)
5-year mortality (women)
Heart Failure*
1950-1969
1970-1979
1980-1989
1990-1999
30%
41%
33%
28%
28%
28%
27%
24%
70%
75%
65%
59%
57%
59%
51%
45%
All Cancer 38% 37.3%
Breast Cancer
Prostate Cancer
Colon Cancer
14.1%
2.4%
38.6%
How Important is Dose Titration?
Titrate as Tolerated to Doses Titrate as Tolerated to Doses Titrate as Tolerated to Doses Titrate as Tolerated to Doses
Achieved in Clinical Achieved in Clinical Achieved in Clinical Achieved in Clinical TrialsTrialsTrialsTrials
*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
Circ Heart Fail. 2010;3:596-605.
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
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 HFrEFComparison 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
Circ Heart Fail. 2010;3:596-605.
Medical Treatment Total Cohort (n = 15,381)
Aldosterone antagonists % patients treated 36.1
Aldosterone antagonists % patients with contraindicationsor 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
N Engl J Med 2004; 351(20): 2049-57
Baseline Medications: Diuretic ~90%; ACE inhibitor or ARB ~85%, Beta-blocker ~75%, Digoxin ~60%; Spironolactone ~40%
Hydralazine/ISDN: A-HeFTTrial design: 1,050 black patients who had New York Heart Association class III or IV heartfailure 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]
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 Drug
Right Time
Right Dose
Right Patient
Optimal Pharmacotherapy
Right Drug
Right Dose
Right Patient
Right Time
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
– IIIImproved mproved mproved mproved collaboration with pharmacists, medically supervised collaboration with pharmacists, medically supervised collaboration with pharmacists, medically supervised collaboration with pharmacists, medically supervised
nurses, prevention coordinators or hospital nurses, prevention coordinators or hospital nurses, prevention coordinators or hospital nurses, prevention coordinators or hospital specialistsspecialistsspecialistsspecialists
• 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