Cardiovascular Guideline-Driven Pharmacotherapies...

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:


Right Drug

Right Time

Right Dose

Right Patient

Optimal Pharmacotherapy

Guideline-Driven Pharmacotherapy:


• 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.



“The eye cannot see what the mind does not

know”- Anonymous



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


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)


Dosing of Beta-blockers in HFrEF Trials

(The Reality)Comparison of Medical Therapy Dosing in Outpatients Cared for in Cardiology





B-blocker % patients treated 86

B-blocker % patients with contraindications or intolerance 6.8



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





Aldosterone antagonists % patients treated 36.1

Aldosterone antagonists % patients with contraindicationsor intolerance

17.7



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?



Knowledge that the guidelines exist is

insufficient but so is familiarity with the

guidelines

Cardiovascular Guideline-Driven Pharmacotherapy:


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

Cardiovascular Guideline-Driven Pharmacotherapies...

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