Debate advances in hf ofili

1. 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

2. ATLANTA UNIVERSITY CENTER
combined faculty of ~ 1000 with a student enrollment
of over 10,000, from across the US and over 50 countries

3. 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

4. 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

5. 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.“

6. Equality vs. Equity

7. 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.

8. 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

9. Heart Failure is Associated with
Neurohormonal Excess and Nitric Oxide
Insufficiency
Endothelial Nitric OxideNeurohormones
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

11. 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
100Survival(%)
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

12. n=32
6.2
All-Cause
Mortality (%)
P=0.012
Placebo + Standard TherapiesFDC 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

13. AHEFT: Impact on Ventricular
Remodeling

14. 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.

15. Ten Years After AHEFT: Have We
Advanced Health Equity?

16. Any degree of uncer tainty a physician may have
relative to the condition of a patient can contribute
to disparities in treatment.
Smedley B. et al, IOM March 2002
McMur ray J. et al NEJM 2014;371(11):993-1004

17. 0
16
32
40
24
8
Enalapril
(n=4212)
360 720 10800 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
Kaplan-MeierEstimateof
CumulativeRates(%)
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

18. 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

19. Paradigm
Shifts in
Heart-Failure
Therapy — A
Timeline
Sacks et al
NEJM;
September 11,
2014 Vol. 371
No. 11

20. 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

21. September 11, 2014; 371:1062-1064

22. 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

23. Equality vs. Equity in Heart Failure Care
ONE size
for ALL
Clinical trials
Without
Race/Ethnici
ty
impact on
efficacy/
side effects
Right size
Clinical trial of
novel drug
incorporate
evidence
based
Background
therapy

24. 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