Advances in Heart Failure For African Americans:

Paradigm Shift or Paradigm Drift?

Elizabeth O. Ofili, MD, MPH, FACC

Professor of Medicine (Cardiology)

Senior Associate Dean, Clinical and Translational Research

Director, Clinical Research Center

Morehouse School of Medicine

Atlanta, Georgia

Email: eofili@msm.edu

ATLANTA UNIVERSITY CENTER

combined faculty of ~ 1000 with a student enrollment

of over 10,000, from across the US and over 50 countries

I N S T I T U T E O F M E D I C I N E (IOM)

Shaping the Future for Health

National Academy of Sciences; 2002. http://www.nap.edu/catalog/10260.html

Health Disparities

A health disparity is a difference in health outcomes across subgroups

of the population. Health disparities are often linked to social, economic,

or environmental disadvantages (e.g., less access to good jobs, unsafe

neighborhoods, lack of affordable transportation options).

Health disparities adversely affect groups of people who have

systematically experienced greater obstacles to health on the basis of

their racial or ethnic group, religion, socioeconomic status, gender, age,

mental health, cognitive, sensory, or physical disability, sexual

orientation or gender identity, geographic location, or other

characteristics historically linked to discrimination or exclusion.

“Of all the forms of inequality, injustice in health care is the most shocking and inhumane.” Martin Luther

King, Jr

“Missing Persons: Minorities in the Health Professions” Louis Sullivan, President Emeritus Morehouse

School of Medicine, 17th Secretary, US Department of Health and Human Services

“What If We Were Equal?” “ If we closed the Black-White Mortality Gap, over 83,000 dealths per year will

be eliminated” David Satcher, 16th US Surgeon General; Past President, Morehouse School of Medicine

What is Health Equity

Healthy People 2020 defines health equity as "attainment of the highest level of health for all people. Achieving health equity requires valuing everyone equally with focused and ongoing societal efforts to address avoidable inequalities, historical and contemporary injustices, and the elimination of health and health care disparities."

Achieving health equity requires valuing everyone equally with focused and ongoing societal efforts to address avoidable inequalities, historical and contemporary injustices, . . .

. . . To eliminate health and health care disparities and attain the highest level of health for all people.“

Equality vs. Equity

Heart Failure Disparities in

African American Patients

• The Prevalence of HF is higher in African Americans than in Caucasians

• HF has a more malignant natural history in African American patients

– Occurs at an earlier age1

– Associated with more advanced left ventricular disease at diagnosis1

• Differing etiology in African Americans

– More likely to be associated with a history of hypertension1

– Incidence of myocardial infarct is consistently lower1

• Worse prognosis in African Americans

– Higher rate of hospitalization than in Caucasian patients2

– Higher mortality rate than in Caucasians2

1. Yancy CW. J Card Fail. 2000;6:183-186.

2. Yancy CW. J Card Fail. 2003;9:S210-S215.

Modifiable risk

factors

Hypertension, diabetes, obesity, LVH, smoking, and chronic

kidney disease are more common in AAs

Neurohormonal

imbalances

and endothelial

dysfunction

Derangements in the renin-angiotensin-aldosterone and

adrenergic axes as well as impaired endothelial function

are more common in AAs

Genetic

polymorphisms

Racial disparity may be the result of several polymorphisms

associated with the risk of HF (beta 1 adrenergic receptor,

alpha 2c receptor, aldosterone synthase, G protein,

transforming growth factor beta, nitric oxide [NO] synthase,

and transthyretin)

Socioeconomic

factors and quality of

care

Low socioeconomic status and discrimination from health

care providers serve as barriers to attaining treatment goals

in AAs

Why Are African Americans More at Risk for

Heart Failure? • Mechanism of HF and responses to pharmacologic therapy among AAs may

differ from those among other races1-3

1. Bahrami H, Kronmal R, Bluemke DA, et al. Differences in the incidence of congestive heart failure by ethnicity: the multi-ethnic study of atherosclerosis. Arch Intern Med. 2008;168(19):2138-2145.

2. Yancy CW. Heart failure in African Americans: unique etiology and pharmacologic treatment responses. J Natl Med Assoc. 2003;95(1):1-9.

3. Yancy CW. Heart failure in African Americans: a cardiovascular enigma. J Card Fail. 2000;6(3):183-186. 4. Sharma A, Colvin-Adams M, Yancy CW. Heart failure in African Americans:

Disparities can be overcome. Cleve Clin J Med. 2014;81(5):301-311.

Sourced from Sharma A, Colvin-Adams M, Yancy CW.. Heart failure in African Americans: Disparities can be overcome. Cleve Clin J Med. 2014;81(5):301-311.4

Heart Failure is Associated with

Neurohormonal Excess and Nitric Oxide

Insufficiency

Endothelial Nitric Oxide Neurohormones

Neurohormonal Antagonists

• Beta Blockers

• Renin-Angiotensin Antagonists

• Aldosterone Blockers

Nitric Oxide Enhancment (NOE)

• Fixed-dose combination ISDN/HYD

• Omapatrilat ( Dual ACE and NEP inh)

• Angiotensin-Neprilysin Anatagonist

N=1050

Fixed-dose I/H 518 463 407 359 313 251 13

Placebo 532 466 401 340 285 232 24

Taylor AL et al. N Engl J Med. 2004;351:2049-2057.

Days Since Baseline Visit Date

A-HeFT: All-Cause Mortality

0 100 200 300 400 500 600 85

90

95

100 S

urvi

val (

%)

P=0.01

Fixed Dose Isosorbide/Hydralazine

Placebo

Hazard ratio=0.57 43% Decrease

Primary Efficacy Endpoint – Composite score: All-Cause Mortality;

First HF Hospitalization; Change in QoL at 6 months relative to baseline

n=32

6.2

All-Cause

Mortality (%)

P=0.012

Placebo + Standard Therapies FDC I/H + Standard Therapies

First HF

Hospitalization (%)

P<0.001 P<0.01

Patient Reported

Functional Status

n=130

24.4 10.2

n=54

10

30

20

-8

0

0

15

10

5 16.4

n=85

n=532

n=518 -4

-2

-6

Taylor AL et al. N Engl J Med. 2004;351:2052.

AHeFT: Trial Summary N=1050

AHEFT: Impact on Ventricular

Remodeling

2013 ACC/AHA Guideline: HYD and ISDN

The combination of HYD and ISDN is

recommended for African Americans with

NYHA class III–IV HFrEF on GDMT – IA

A combination of HYD and ISDN can be

useful with HFrEF who cannot be given ACE-

Is or ARBs – IIa B

Yancy CW et al. J Am Coll Cardiol. 2013:62:e147-e239.

Ten Years After AHEFT: Have We

Advanced Health Equity?

Any degree of uncertainty a physician may have

relative to the condition of a patient can contr ibute

to disparities in treatment.

Smedley B. et al, IOM March 2002

McMur ray J. et al NEJM 2014;371(11):993-1004

0

16

32

40

24

8

Enalapril (n=4212)

360 720 1080 0 180 540 900 1260

Days After Randomization

4187

4212

3922

3883

3663

3579

3018

2922

2257

2123

1544

1488

896

853

249

236

LCZ696

Enalapril

Patients at Risk

1117

Kap

lan

-Meie

r E

sti

mate

of

Cu

mu

lati

ve R

ate

s (

%)

914

LCZ696 (n=4187)

PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)

HR = 0.80 (0.73-0.87)

P = 0.0000002

Packer M., et al. For PARADIGM Investigators

LCZ696 (n=4187)

Enalapril (n=4212)

P Value

Prospectively identified adverse events

Symptomatic hypotension 588 388 < 0.001

Serum potassium > 6.0 mmol/l 181 236 0.007

Serum creatinine ≥ 2.5 mg/dl 139 188 0.007

Cough 474 601 < 0.001

Discontinuation for adverse event 449 516 0.02

Discontinuation for hypotension 36 29 NS

Discontinuation for hyperkalemia 11 15 NS

Discontinuation for renal

impairment 29 59 0.001

Angioedema (adjudicated)

Medications, no hospitalization 16 9 NS

Hospitalized; no airway

compromise 3 1 NS

Airway compromise 0 0 ----

PARADIGM-HF: Adverse Events Commentary: The trial randomized only patients who successfully completed a single-blind run-in phase consisting of enalapril for two weeks

and then LCZ699 for twice that long—all after being stable for at least a month on either an ACE inhibitor or

angiotensin-receptor blocker (ARB). Of the 10 521 entering the run-in phase, >2000 dropped out, mostly because they couldn't

tolerate one of the two agents, often because of hypotension

Packer M., et al. For PARADIGM Investigators

Paradigm

Shifts in

Heart-Failure

Therapy — A

Timeline

Sacks et al

NEJM;

September 11,

2014 Vol. 371

No. 11

Dr Lynne Warner Stevenson(Boston MA): "I don't believe it is time [for ARNIs] to

replace ACE inhibitors or ARBs," given all the patients who didn't tolerate the drug

or didn't meet the inclusion criteria”

"The advent of LCZ[696] enriches our respect for the complexity of our patients'

individual responses. I'm not really sure which actions of ACE inhibitors are the

most important for which patients. I'm not [even] sure which actions of beta-

blockers are most important for which patients. And I'm certainly not sure of all the

hormones affected by LCZ[696] or which are going to be the most important for

each patient. These results should inspire us to do new research on these

kinds of individual responses and the challenge of optimizing our therapies

in patient-centered ways,”

"I don't think that LCZ[696] is ready for a level I indication; that is a higher bar,”

Dr John Cleland( London, UK): “Eight thousand patients is a lot, but not enough

to answer every question about the new agent; We are going to need more clinical

trials.”

PARADIGM-HF at HFSA Sessions: September 25, 2014

MEDSCAPE-News from the: Heart Failure Society of America (HFSA) 18th Annual Scientific Meeting

September 11, 2014; 371:1062-1064

Advances in Heart Failure For African

Americans: Paradigm Shift or Paradigm Drift? • A decade after the landmark AHEFT Trial, African American

patients are not receiving guideline based medical therapy

• Clinical trials of novel heart failure therapies should integrate guideline based therapies across ALL demographic groups of heart failure patients, including African Americans

Advancing heart failure treatment for African American patients requires a Paradigm shift to advance health equity

Ofili2015

Equality vs. Equity in Heart Failure Care ONE size for ALL Clinical trials Without Race/Ethnicity impact on efficacy/ side effects

Right size Clinical trial of novel drug incorporate evidence based Background therapy

Thank you!!!!

www.msm.edu

Mission: Leading the Creation and Advancement of Health Equity #1 in Social Mission among US medical schools (Annals of Internal

Medicine, June 2010) Announcing: Association of Black Cardiologists/Morehouse School of Medicine Cardiovascular Disease Registry