Ethnic differences - intrinsic and extrinsic factors

Study populations - Ethnic differences –
intrinsic and extrinsic factors.
What impact in Heart Failure outcome
trials ?
Faiez Zannad
CIC-INSERM, U 961
Hypertension and Heart Failure Division
department of Cardiology,
University hospital of Nancy, France
DGOS

Disclosures
Faiez Zannad
• Research Grants
• BG Medicine
• Roche Diagnostics
• Consultancy
• Novartis, Resmed, Pfizer, Boston Scientific, Takeda,
Servier, Boehringer, Bayer, Relypsa, J&J.

Pitt B et al. N Engl J Med. 1999; 341: 709-717
3
RALES
Only one HF clinical trial that Japan has ever participated.
However, the number of enrolled patients was as few as 14.
1,663 patients were randomized from 15 countries

China
Variations by Etiology
Rheumatic heart disease 19%
IHD 46%
Dilated cardiomyopathies 8%
Hypertensive 13%
Congenital heart dis. 3%
Other CVD 7%
Based on nationwide survey of 10,000
patients admitted for heart failure in China,
Year 2000
Zhengming Chen (HF Trialists 2009)

Patterns of hospital treatment for heart
failure in China, 2000
Diuretics 19%
Digitalis 40%
Nitrate 53%
Ca ++ antagonists 10%
β-blocker 19%
ACE-I 40%
ARB 4%
Aldoseterone antagonists 20%
Dopamine 14%
Zhengming Chen (HF Trialists 2009)

India - Mortality by
socio-economic strata
Rich Upr mid Lowr mid Poor P
Death rate
(un-adj)
5.5 5.9 6.5 8.2

Comparison of Trials and Registries
OPTIMIZE
N=48,612
ADHERE
N=105,388
Mean age 73.1 (14.2) 72.6 (13.9) 71
% African
American
18% 20%
% Male 48% 48% 53%
Mean LVEF 39 (17.6) 34.4 (16.1)
EuroHeart Failure
Survey (overall)
N=10,701
CAD 50% 57%
HTN 71% 73% 53%
DM 42% 44% 27%
Renal
insufficiency
Atrial
fibrillation
20% 30% 17%
31% 31% 42%

Clinical Outcomes: Registries and
Trials
OPTIMIZE-
HF
ADHERE
EuroHeart
Failure
Survey
Length of Stay, Median (days) 4 (3,7) 4.1 11
In-Hospital Mortality (%) 1,834 (3.8) 4.0
739
(6.9%)
60- to 90-Day Readmission Rate
(%)
60- to 90-Day Mortality Rate (%)
(includes in-hospital deaths)
1,715 (29.6) NA
571 (9.9) NA
24.2%
(90-day)
1408
(13.5%)

Regional differences of specific
complications in Diabetes in ADVANCE.
Clarke PM et al Plos Medicine 2010

Contributions of specific complications to
total hospital use during the ADVANCE
study, in Diabetes, by region.
Clarke PM et al Plos Medicine 2010

Heart failure event rate/year
Asia: 0.4
Europe + NZ: 1.0%

Efficacy of Vasopressin antagonism
in hEart failuRE: outcome Study with
Tolvaptan (EVEREST)

EVEREST
Key Entry Criteria
Inclusions
• Hospitalization for HF 1+)
– Dyspnea
Exclusions
• Recent or planned revascularization or device implant
• STEMI during hospitalization
• Systolic BP 3.5 mg%; K >5.5 mEq/L; Hgb

EVEREST
Different clinical background
15
Blair JE, Zannad F, Konstam MA, et al. JACC. 2008;52(20):1640-8
J E Blair et al. JACC 2008

Etiology in Brazil : Chagas disease
Probability of survival relative to the etiology of HF
Freitas HFG. Int J Cardiol 2005;102:239-247.

EVEREST
Different comorbidities
17
Blair JE, Zannad F, Konstam MA, et al. JACC. 2008;52(20):1640-8
J E Blair et al. JACC 2008

EVEREST
Different severity
Blair JE, Zannad F, Konstam MA, et al. JACC. 2008;52(20):1640-8
18 J E Blair et al. JACC 2008

EVEREST
Different treatment
19
Blair JE, Zannad F, Konstam MA, et al. JACC. 2008;52(20):1640-8
J E Blair et al. JACC 2008

EVEREST: ALL Cause Mortality
Blair JE, Zannad F, Konstam MA, et al. JACC. 2008;52(20):1640-8

EVEREST:
CV Death + HF Hospitalozation
Blair JE, Zannad F, Konstam MA, et al. JACC. 2008;52(20):1640-8

EVEREST
Cumulative mortality (24 month FU) vs. North America
after adjustment for baseline differences
Overall mortality
CVD + hospitalization
South America
South Americans die
more
Western Europe
Eastern Europe
0 1.0 1.5 2.0
HR (0.95% CI)
0 1.0 1.5 2.0
HR (0.95% CI)
Eastern
Europeans
hospitalized
less
22
Blair JE, Zannad F, Konstam MA, et al. JACC. 2008;52(20):1640-8

International differences in LOS and 30-day all-cause
readmission rates (ASCEND)
among patients discharged alive and LOS

International differences in LOS and 30-day all-cause
readmission rates (ASCEND)
among patients discharged alive and LOS

Relationship between initial LOS and 30-day
readmission (ASCEND)
Level of
hierarchical
model
Patient
Site
Country
Effect
All-cause
readmissions
Pt
estimate
95% CI
P-
value
0.975 0.956 0.995 0.015
HF Readmissions 0.951 0.924 0.980 0.001
All-cause
readmissions
0.934 0.884 0.985 0.013
HF Readmissions 0.902 0.838 0.971 0.006
All-cause
readmissions
0.849 0.749 0.963 0.013
HF Readmissions 0.796 0.669 0.946 0.012

Relationship between initial LOS and 30-day
readmission – US vs OUS (ASCEND)
Level of
hierarchical
model
Country
US only
Effect
All-cause
readmissions
Pt
estimate
95% CI p-value
0.849 0.749 0.963 0.013
HF Readmissions 0.796 0.669 0.946 0.012
All-cause
readmissions
0.915 0.842 0.990 0.034
HF Readmissions 0.867 0.773 0.971 0.014

•America vs. EU
•No difference in death rate.
• Higher All cause hospitalizations (non CV hosp),
• Persisted even after adjustment for baseline imbalance
Pitt B; Zannad F; Gheorghiade M, et al., Int J Cardiol.,2009

Pitt B; Zannad F; Gheorghiade M, et al., Int J Cardiol.,2009
Subgroup analyses based on regions have
rarely changed the main results of HF trials
(No interaction found)
Subgroup analysis based on regions
No change in the main results (No interaction found)
EPHESUS

Baseline Characterístics
Europe
R o W
Age (y) 64.7 60.1
Men % 76 76
IHD % 68 67
NYHA II, % 49 49
NYHA III/IV, % 51 51
AMI % 56 56
Diabetes, % 36 31
Hypertension, % 67 66

http://www.accessdata.fda.gov
Subgroup analysis based on regions
Important change in the main results (interaction found)
MERIT-HF The FDA sub-analysis
All cause Death
Death + Hosp Death + HF Hosp

Survival analysis of beta-blocker trials by US
vs. non-US enrollment
O’Connor et al, ACC 2010

Massie B. J Am Coll Cardiol, 2011; 58:923-924
“The provocative major finding of the analysis is
that there appears to be a lesser survival benefit of
BB that were studied in North American patients
than in patients enrolled in the rest of the world”
“However, most important, one cannot exclude the
play of chance in these findings”

Exon 7 NOS3 in afro-american (AA) pts
A-HeFT and GRACE registry
NOS3
exon 7
GRACE
Non-AA
GRACE
A-A
A-
HeFT
Asp-Asp
(%)
Asp-Glu
(%)
Glu-Glu
(%)
14 2 1
45 31 20
41 67 79
Taylor A et al , Circulation 2007
McNamara DM et al. Journal of
Cardiac Failure Vol. 15 No. 3 2009

Endothelial nitric oxide synthase gene
polymorphisms
+1
26 exons
-1468 -922 -786 intron 4a/b exon 7 intron 13 intron 18 intron 23
(Т/А) (A/G) (T/C) (27 bp repeat) (G894T) (CA repeat) (A/C) (G/T)
(more than 15 polymorphisms have been identify in eNOS gene)
‣ Т-786С polymorphism in eNOS gene promoter
‣ 27-base pair (bp) repeat polymorphism in intron 4
‣ G894T (Glu 298 Asp) polymorphism in exon 7

The frequency of CC genotype of eNOS gene
promoter in different populations (controls)
%
20
16
12
8
4
0
Italy UK Spaine France Canada Ukraine Japan
*
1. Colombo MG, et al. // Clin. Chem. (2003)Vol. 49. – P.389-395; 2. Jeerooburkhan N, et al.// Hypertension.(2001)Vol. 38. – P. 1054-1061;
3. Alvarez R., et al. // Nitric Oxide.( 2001)Vol.5, N4. - P.343-348; 4. Poirier O, et al.// Eur. J. Clin. Invest.(1999) Vol. 29. – P.284–290;
5. Hyndman ME, et al.// Hypertension. (200)Vol. 39. – P. 919-925; 6. Iwai N, et al. // Circulation. (1999)Vol. 100. – P.2231-2236.

The a 2C
Del322-325 and b 1
Arg389
receptors act synergistically to increase
the risk of heart failure in blacks
Small, K. et al. N Engl J Med 2002;347:1135-1142

BEST
Therapeutic response (CV Mortality) to bucindolol
was strongly influenced by 2C receptor genotype.
Bucindolol A2
Placebo A2
Bristow, M et al. Circ Heart Fail. 2010;3:21-28.

Conclusions
• Despite relatively strict inclusion/exclusion criteria, patient
populations remained heterogeneous among regions in
– Patient baseline characteristics,
– Therapies, and medications
– and also in outcome.
• Differences are most likely related to varying
– HF epidemiology, etiology, socio economic status
– health care systems, access to health resources
• Rather than regional differences, genetic variations may
be more relevant

Conclusions
• Globalization of trials is a necessity
• Regional differences should not play against
globalization of clinical trials
• Subgroup analyses based on regions have
rarely changed the main results of HF trials (No
interaction found)
• Balance among regions represented in a trial is
important in order to avoid over-representation
of a region and interpretation bias.