Examples of ethnicity and geography issues in global clinical trials ...

Examples of
ethnicity and geography issues
in global clinical trials
of ACS and AF
Lars Wallentin
Professor of Cardiology,
Chief Researcher Cardiovascular Science
Uppsala Clinical Research Centre,
Uppsala University, Uppsala, Sweden

Enrollment
37 countries, 818 sites, 12,944 patients
Norway: 251
Poland: 561
Sweden: 346
Finland: 119
Hungary: 266
Canada:
591
United States:
2772
Puerto Rico: 41
Colombia: 275
Peru: 11
Denmark: 205
U.K.: 463
Netherlands: 471
Belgium: 153
Germany: 911
Portugal: 189
France: 441
Spain: 379
Brazil: 284
Czech Rep: 496
Switzerland:
211
Turkey: 164
Malaysia: 52
Singapore: 26
China: 219
Japan: 276
South Korea: 127
Taiwan: 219
Hong Kong: 17
Chile: 148
Austria: 319
Italy: 764
South Africa: 207
Australia:
235
Argentina: 130
Israel: 410
New Zealand: 195

Trial Design
Placebo
NSTE Acute Coronary
Syndromes
1:1
Randomized
Double-blind
Key inclusion criteria
• Within 24 hrs of symptoms
• biomarkers or ECG changes
• 1 other high-risk feature
Vorapaxar
Loading: 40 mg
Maintenance: 2.5 mg daily
Follow-up: 1, 4, 8, 12 months, then every 6 months
Standard of care based on practice guidelines
Efficacy Endpoints
Primary: CV death, MI, stroke, hospitalization for ischemia, urgent revascularization
Key Secondary: CV death, MI, stroke
Bleeding Endpoints: GUSTO moderate or severe and clinically significant TIMI bleeding

Event Rate
Bleeding Outcomes
GUSTO Moderate/Severe
Primary Endpoint
CV Death, MI, Stroke, Hospitalization for Ischemia, Urgent Revascularization
ICH
Placebo
Vorapaxar
2-year KM rate 5.2% 7.2%
20%
15%
Placebo
HR (95% CI): 3.39 (1.78, 6.45)
P-value

Subgroups
GUSTO Moderate/Severe
Primary Endpoint
Vorapaxar
better
Placebo
better
Vorapaxar
better
Placebo
better

Subgroups
GUSTO Moderate/Severe
Primary Endpoint
Vorapaxar
better
Placebo
better
Vorapaxar
better
Placebo
better

PLATO study design
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)
Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)
Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
6–12-month exposure
Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid;
CV = cardiovascular; TIA = transient ischaemic attack

PLATO – a global trial
Argentina
Australia
Austria
Belgium
Brazil
Bulgaria
Canada
China
Czech
Republic
Denmark
Finland
France
Georgia
Germany
Greece
Hong Kong
Hungary
India
Indonesia
Israel
Italy
Malaysia
Mexico
The
Netherlands
Norway
Philippines
Poland
Portugal
Romania
Russia
Singapore
Slovakia
Spain
Sweden
Switzerland
South Africa
South Korea
Taiwan
Thailand
Turkey
Ukraine
United
Kingdom
United
States

Cumulative incidence (%)
PLATO: primary endpoint:
K-M estimate of time to major CV event
(composite of CV death, MI or stroke)
13
12
11
10
9
8
7
6
5
4
3
2
1
0
Clopidogrel
Ticagrelor
(HR, 0.84; 95% CI, 0.77-0.92; P

Primary endpoint in predefined subgroups (1)
Characteristic
Hazard Ratio
(95% CI)
Total
Patients
KM % at
Month 12
Ti.
Cl.
HR (95% CI)
Overall Treatment Effect
Primary Endpoint
18,624 9.8 11.7 0.84 (0.77, 0.92)
N ST elevation/LBBB at randomization
No
11,074 10.1 12.3 0.83 (0.74, 0.93)
Yes
7544 9.4 10.8 0.87 (0.75, 1.01)
First Troponin I
Positive
15,089 10.3 12.3 0.85 (0.77, 0.94)
Negative
2968 7.0 7.0 1.00 (0.75, 1.32)
Time from Index Event to first IP

Primary endpoint in predefined subgroups (3)
Characteristic
Hazard Ratio
(95% CI)
Total
Patients
KM % at
Month 12
Ti.
Cl.
HR (95% CI)
Antiplatelet Therapy Prior to Index Event
Clopidogrel ± ASA
1397 15.8 17.8 0.95 (0.73, 1.24)
ASA
5024 11.8 14.0 0.84 (0.71, 0.98)
None
12,147 8.2 10.0 0.82 (0.73, 0.93)
ASA on Day of Rand.
No
927 11.6 13.8 0.87 (0.60, 1.27)
Yes
17,697 9.7 11.6 0.84 (0.77, 0.93)
GPIIb/IIIa (IE to End of Index Hosp.)
No
13,562 9.7 11.9 0.82 (0.74, 0.92)
Yes
5062 10.0 11.1 0.90 (0.76, 1.07)
Race
Caucasian
Black
17,077
229
9.5
13.0
11.2
19.6
0.85 (0.77, 0.94)
0.63 (0.32, 1.23)
Oriental
1096 12.5 14.8 0.87 (0.62, 1.21)
Other
221 14.4 21.4 0.63 (0.33, 1.21)
Weight by Gender-specific Median
Males

Primary endpoint in predefined subgroups (4)
Characteristic
Ticagrelor better
Hazard Ratio
(95% CI)
Clopidogrel better
Total
Patients
KM % at
Month 12
Ti. Cl.
HR (95% CI)
Final Diagnosis
Unstable angina
3112 8.6 9.1 0.96 (0.75, 1.22)
NSTEMI
7955 11.4 13.9 0.83 (0.73, 0.94)
STEMI
7026 8.5 10.1 0.84 (0.72, 0.98)
Other
489 9.1 14.7 0.58 (0.34, 1.00)
Mod. Isoenzyme 3A (Rand.)
No
16,717 9.7 11.6 0.84 (0.77, 0.93)
Yes
1907 10.4 12.1 0.85 (0.65, 1.12)
Heparin Use (IE to end of Index Hosp.)
No
6696 10.4 12.6 0.84 (0.73, 0.98)
Yes
11,928 9.5 11.1 0.85 (0.75, 0.95)
Lipid-Lowering Drugs (Rand.)
No
3768 11.0 11.2 1.02 (0.83, 1.24)
Yes
14,856 9.5 11.8 0.80 (0.73, 0.89)
Beta Blockers (Rand.)
No
4564 9.0 11.6 0.79 (0.65, 0.95)
Yes
14,060 10.1 11.7 0.86 (0.78, 0.96)
ACE Inhibitors (Rand.)
No
8102 9.4 10.6 0.90 (0.78, 1.03)
Yes 10,522 10.1 12.5 0.81 (0.72, 0.91)
Angiotensin II Receptor Blockers (Rand.)
No
16,981 9.6 11.6 0.83 (0.76, 0.92)
Yes 1643 11.8 12.8 0.96 (0.72, 1.28)
Calcium Channel Blockers (Rand.)
No
15,888 9.6 11.3 0.86 (0.78, 0.95)
Yes
2736 10.8 13.8 0.76 (0.61, 0.95)
Proton Pump Inhibitors (Rand.)
No
12,249 9.2 11.0 0.83 (0.74, 0.93)
Yes 6375 11.0 12.9 0.86 (0.75, 1.00)
0.2
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057 and
supplementary tables
0.5 1.0 2.0
P value
(Interaction)
0.41
0.93
0.98
0.04
0.40
0.27
0.37
0.33
0.69

Primary endpoint in predefined subgroups (2)
Characteristic
Revascularization History of CABG
No
Yes
Previous TIA/Non-hemorrhagic Stroke
No
Yes
Age Group

Geographic Regions
CV Death, MI, Stroke
Geographic
region
Total
patients
KM at month 12
Tic
Clop
HR (95% CI)
Interaction
p-values
Asia /
Australia
1714
11.4
14.8
0.80 (0.61, 1.04)
Central America /
South America
Europe /
Middle East / Africa
1237
13859
15.2
8.8
17.9
11.0
0.86 (0.65, 1.13)
0.80 (0.72, 0.90)
0.045
0.01
North America
1814
11.9
9.6
1.25 (0.93, 1.67)
0.5 1.0 2.0
Ticagrelor
better
Clopidogrel
better

No Systematic Errors
• US and ROW exhibited similar data quality based
on query rates
• Pharmacokinetic substudy samples of US
ticagrelor patients had ticagrelor in their plasma
• US patients had lower study drug compliance
(62% vs. 85%) and higher study drug
discontinuation (31% vs. 22%) but similar by
treatment group
• No bias observed in event reporting

Baseline Characteristics:
US and Rest of the World
US
(n = 1,413)
ROW
(n = 17,211)
Age, years* 61 (53–70) 62 (54–71)
Female sex 406 (28.7) 4882 (28.4)
Weight, kg* 87 (75–100) 80 (70–89)
Hypertension 1000 (70.8) 11,183 (65.0)
Diabetes mellitus 472 (33.4) 4190 (24.4)
Prior MI 387 (27.4) 3437 (20.0)
Prior PCI 415 (29.4) 2077 (12.1)
Prior CABG 236 (16.7) 870 (5.1)
Smoking: Non-smoker
Ex-smoker
416 (29.5)
481 (34.1)
6840 (39.8)
4195 (24.4)
Persistent ST elevation 217 (15.4) 6791 (39.5)
Troponin positive 1176 (83.2) 13,913 (80.8)
Data are n (%) or * median (1st–3rd quartile).

High-dose Aspirin Use: Landmark Time Points
75
69
61
58 57
55
ROW
53 52
US
50
47
%
36,9
25
3,9 2,9 2,8 2,4 1,5 1,4 1,3
0
Rand
Day
2
Day
4
Day
9
Day
30
Day
60
Day
90
Day
180
Landmark Timepoints
ASA:

Effect Modifier Analysis
Entire cohort analysis
Day-4 landmark analysis

Primary Efficacy Outcome
US and Non-US and by ASA Dose
*Hazard ratio not calculated due to small number of events.

Landmark Analyses
Region and ASA
Dose
ASA:

Summary
• In PLATO, ticagrelor reduced CV death, MI, and stroke
• In a pre-specified analysis of treatment effect across regions, the
hazard ratio favored ticagrelor in the rest of the world but not in
North America
• Statistical analyses by two independent groups identified ASA
maintenance dose as a potential explanation of the regional
differences
• The play of chance is another possible explanation
• These analyses and current ACS treatment guideline
recommendations support that, during potent P2Y 12 inhibition with
ticagrelor, low maintenance aspirin dose is likely associated with
favorable outcomes

RE-LY: A Non-inferiority Trial
Atrial fibrillation
≥1 Risk Factor
Absence of contra-indications
951 centers in 44 countries
Blinded Event Adjudication
R
Open
Blinded
Warfarin
adjusted
(INR 2.0-3.0)
N=6022
Dabigatran
Etexilate
110 mg BID
N=6015
Dabigatran
Etexilate
150 mg BID
N=6076
Mean TTR 64%
Wallentin L., et al. Lancet 2010; in press.
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation

RE-LY ® – participating countries
Connolly SJ., et al. N Engl J Med 2009; 361:1139-1151.
Additional recruitment in10 other countries n = 513
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation

Cumulative hazard rates
Time to first stroke / SSE
0.05
0.04
0.03
0.02
Warfarin
Dabigatran etexilate 110 mg
Dabigatran etexilate 150 mg
RR 0.90
(95% CI: 0.74–1.10)
p

Primary Outcome Sub-groups (3)
Dabigatran110 vs. WARFARIN
Dabigatran150 vs. WARFARIN
P(INTER)
P(INTER)
NORTH AMERICA
SOUTH AMERICA
WESTERN EUROPE
CENTRAL EUROPE
SOUTH ASIA
EASTERN ASIA
OTHER REGION
0.91
0.11
ASA
NO ASA
0.69
0.95
AMIODARONE
NO AMIODARONE
0.07
0.14
PPI
NO PPI
0.34
0.16
0.50 1.00 1.50
0.50 1.00 1.50
Dabigatran better
Warfarin better
Dabigatran better
Warfarin better

Country distribution of mean TTR

% per year
Stroke / SSE
According to center based time in therapeutic range (cTTR)
Q1: cTTR < 57.1% Q2: cTTR 57.1-65.5%
Q3: cTTR 65.5 – 72.6% Q4: cTTR > 72.6%
2,4
1,8
* Interaction p-value (D 110mg BID vs W.) = 0.90
† Interaction p-value (D 150mg BID vs W.) = 0.20
*Interaction p evaluated by a multivariable approach
with center based TTR as a continuous variable.
1,2
0,6
W D* D †
110 150
W D* D †
110 150
W D* D †
110 150
W D* D †
110 150
0
Wallentin L., et al. Lancet 2010; in press.
Q1 Q2 Q3 Q4
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation

% per year
All cardiovascular events
According to cTTR
All cardiovascular events include vascular
events, death and major bleeding
Q1: cTTR < 57.1% Q2: cTTR 57.1-65.5%
Q3: cTTR 65.5 – 72.6% Q4: cTTR > 72.6%
10
9
8
* Interaction p-value (D 110mg BID vs W.) = 0.04
† Interaction p-value (D 150mg BID vs W.) = 0.007
*Interaction p evaluated by a multivariable approach
with center based TTR as a continuous variable.
7
6
5
4
3
W D* D †
W D* D †
W D* D †
W D* D †
2
110 150
110 150
110 150
110 150
1
0
Wallentin L., et al. Lancet 2010; in press.
Q1 Q2 Q3 Q4
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation

Ethnicity and geography issues
in global clinical trials of ACS and AF
• Play of chance – correction for multiplicity, small patient
numbers in geographical subgroups
• Problems with study performance and procedures in
specific geographical area
• Differences in compliance
• Differences in patient characteristics, co-morbidities,
medical treatments might modulate the treatment effect
• Differences in pharmacogenetics, response genetics
• Seldom biological rationale for geographical differences

Ethnicity and geography issues
in global clinical trials of ACS and AF
• Relative effect in overall trial most likely the
true effect for all subgroups
• Subgroup findings are hypothesis generating
for exploration in future trials
• Subgroup findings might lead to tailoring of
treatment if consistent and based on
plausible biological rationale