1. The Conduit Artery Functional Evaluation (CAFE) Study Principal Results
The CAFE investigators
Bryan Williams, Peter S. Lacy,
Simon McG. Thom, Kennedy Cruickshank,
Alice Stanton, David Collier, Alun D. Hughes, Herbert Thurston.
Study Advisor;
Michael O’Rourke
For the ASCOT Investigators

2. CAFE Study Steering Committee
Professor Bryan Williams, MD, FRCP, FAHA
Principal Investigator and Chairman of the Steering Committee
University Department of Cardiovascular Sciences
University of Leicester, Leicester, UK
Dr Peter S. Lacy, PhD
Steering Committee and CAFE Study Coordinator
Professor Kennedy Cruickshank
Clinical Epidemiology Group, University Department
of Medicine, Manchester Royal Infirmary
Manchester, UK
Professor Alice Stanton
Department of Clinical Pharmacology, Royal College of
Surgeons in Ireland, St Stephen’s Green, Dublin, Ireland
Dr David Collier
Department of Clinical Pharmacology, William Harvey
Research Institute, Bart’s & The London, Queen Mary’s
School of Medicine & Dentistry, London, UK
Professor Simon McG Thom Clinical Pharmacology and Therapeutics St. Mary’s Hospital
Imperial College London London, UK
Professor Herbert Thurston University Department of Cardiovascular Sciences University of Leicester, Leicester, UK
ASCOT Sub-Study Committee Liaison:
Prof. Eoin O’Brien, Prof. Mark Caulfield
Study Advisor
Professor Michael O’Rourke
University of New South Wales, Sydney, Australia
Statistical Support, CSRI, Gothenburg, Sweden
B Dahlof, H Wedel, R Chamberlain, NG Pehrsson,
M Molin, A Pivodic, J Lindqvist, A Hagelin
For the CAFE Investigators and ASCOT Investigators

3. Background (1)
Brachial blood pressure is a strong predictor of clinical outcomes in people with hypertension
It is assumed that brachial blood pressure accurately reflects pressures in the central aorta and thus left ventricular load
This assumption may not be valid in all circumstances because different classes of blood pressure–lowering drugs may differentially influence central aortic blood pressures

4. Background (2)
In clinical trials comparing different blood pressure lowering–drugs, clinical outcomes could be influenced by drug effects on central aortic pressures, despite similar effects on brachial blood pressure
This hypothesis required testing in a prospective clinical outcomes trial evaluating 2 different blood pressure– lowering treatment regimens
The Conduit Artery Functional Evaluation (CAFE) study was designed to test this hypothesis as a major substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

5. CAFE Hypothesis Primary Objective
The different blood pressure–lowering regimens in ASCOT (atenolol ± thiazide versus amlodipine ± perindopril) would produce different effects on central aortic pressures and haemodynamics despite similar effects on brachial blood pressure
Secondary Objective
Central aortic pressures would be an important determinant of clinical outcomes
Williams B. and O’Rourke M. J Hum Hypertens. 2001;15(suppl 1):S69-S73.

6. CAFE Study Design
Recruitment from 5 large UK and Ireland ASCOT study centres
Central co-ordinating centre (Leicester, UK)
Recruitment into CAFE commenced when patients were stable after up-titration of ASCOT medication (~1 year after start of ASCOT)
80% patients had more than one tonometry measurement
Average number of tonometry measurements/patient was 3.4
Average follow-up after 1st measurement was 3.0yrs
Circulation. 2006;113:

7. Brachial Blood Pressure
Pulse Wave Analysis
Brachial Blood Pressure
Bone
Artery
Sensor
140 70
Radial
Transfer
function
Central Aortic
140 70

8. CAFE Study Profile 2199 subjects recruited from 5 UK ASCOT centres
126 excluded due to heart rate irregularity/poor waveforms
2073 evaluable
for tonometry
1042 received
amlodipine-based regimen
1031 received
atenolol-based regime
4 subjects incomplete information, 1 alive at last visit, 2 withdrawn consent,
1 lost to follow-up
1 subject incomplete information,
withdrawn consent
1042 assessed on an intention-to-treat basis 1038 complete information
(997 alive, 41 dead)
1031 assessed on an intention-to treat basis 1030 complete information
(989 alive, 41 dead)
Circulation. 2006;113:

9. Baseline Demographics (1)
CAFE
ASCOT
Atenolol-based n=1031
Amlodipine-based n=1042
Atenolol-based n=9639
Amlodipine-based n=9618
Women
189 (18.3%)
208 (20%)
2257 (23.5%)
2258 (23.4%)
Age (years)
62.6 (8.3)
62.9 (8.2)
63.0 (8.5)
White
886 (85.9%)
892 (85.6%)
9170 (95.3%)
9187 (95.3%)
Current smoker
251 (24.3%)
267 (25.6%)
3109 (32.3%)
3168 (32.9%)
SBP mm Hg
159.9 (16.6)
161 (18.4)
163.9 (18)
164.1 (18.1)
DBP (mm Hg)
92.4 (9.6)
92.6 (9.8)
94.5 (10.4)
94.8 (10.4)
Heart rate (bpm)
71.8 (12.3)
71.2 (12.4)
71.8 (12.6)
71.9 (12.7)
BMI (kg/m2)
29 (4.5)
29.1 (4.7)
28.7 (4.5)
28.7 (4.6)
Height (cm)
170.7 (8.7)
170.2 (9.4) NA
Total cholesterol (mg/dL)
224.3 (38.7)
224.3 (42.5)
228.2 (42.5)
LDL-cholesterol (mg/dL)
143.1 (34.8)
146.9 (38.7)
HDL-cholesterol (mg/dL)
50.3 (15.5)
Triglycerides (mg/dL)
159.4 (88.6)
159.4 (8.6)
168.3 (88.6)
Glucose (mg/dL)
110 (38)
112 (38)
Creatinine (mg/dL)
1.08 (0.18)
1.09 (0.19)
1.09 (0.19)
1.09 (0.18)
Need to improve this table – not clear
Circulation. 2006;113:

10. Baseline Demographics (2)
CAFE
ASCOT
Atenolol-based n=1031
Amlodipine-based n=1042
Atenolol-based n=9639
Amlodipine-based n=9618
Medical history
Prior stroke/TIA
76 (7.4%)
101(9.7%)
1063 (11.1%)
1050 (10.9%)
Diabetes
252 (24.4%)
251 (24.4%)
2578 (26.8%)
2567 (26.6%)
LVH (echo or ECG)
237 (23%)
256 (24.6%)
2076 (21.6%)
2091 (21.7%)
Peripheral vascular disease
61 (5.9%)
59 (5.7%)
613 (6.4%)
586 (6.1%)
Other relevant CV disease
22 (2.1%)
27 (2.6%)
486 (5.1%)
533 (5.5)
Mean (SD) # risk factors
3.7 (0.9)
Drug therapy
BP treatment naive
109 (10.6%)
100 (9.6%)
1825 (19%)
1841 (19.1%)
Lipid-lowering therapy
120 (11.6%)
120 (11.5%)
1004 (10.4%)
1046 (10.9%)
Aspirin use
244 (23.7%)
274 (26.3%)
1837 (19.1%)
1851 (19.2%)
Need to improve this table
Circulation. 2006;113:

11. Calcium Channel Blocker Regimen -Blocker Based Regimen
Treatment Algorithm
Calcium Channel Blocker Regimen
-Blocker Based Regimen
Step 1
Amlodipine 5 mg
Atenolol 50 mg
Step 2
Amlodipine 10 mg
Atenolol 100 mg
Step 3
Amlodipine 10 mg + perindopril 4 mg
Atenolol 100 mg + bendroflumethiazide K 1.25 mg
Step 4
Amlodipine 10 mg + perindopril 8 mg (2x4 mg)
Atenolol 100 mg + bendroflumethiazide K 2·5 mg
Step 5
Amlodipine 10 mg + perindopril 8 mg (2x4 mg) + doxazosin gastrointestinal transport system 4 mg
Atenolol 100 mg + bendroflumethiazide K 2·5 mg + doxazosin gastrointestinal transport system 4 mg
Step 6
Amlodipine 10 mg + perindopril 8 mg (2x4 mg) + doxazosin gastrointestinal transport system 8 mg
Atenolol 100 mg + bendroflumethiazide K 2·5 mg + doxazosin gastrointestinal transport system 8 mg
Further treatment to achieve blood-pressure goal outlined at All drugs given orally.
Circulation. 2006;113:

12. Difference (Atenolol-Amlodipine)
Haemodynamic Data
Parameter
Atenolol
Amlodipine
Difference (Atenolol-Amlodipine)
Statistics t-test (P)
Brachial SBP (mm Hg)
133.9 (133, 134.7)
133.2 (132.5, 133.8)
0.7 (-0.4, 1.7)
0.2
Brachial DBP (mm Hg)
78.6 (78.1, 79.1)
76.9 (76.4, 77.4)
1.6 (0.9, 2.4)
<.0001
Brachial PP (mm Hg)
55.3 (54.6, 56)
56.2 (55.6, 56.9)
-0.9 (-1.9, 0)
.06
Heart rate (BPM)
58.6 (58, 59.2)
69.3 (68.6, 69.9)
-10.7 (-11.5, -9.8)
Data: Area under Curve ± 95% CI
Circulation. 2006;113:

13. Brachial and Central Aortic Systolic Blood Pressure (± 95% CI)
Brachial SBP
Diff Mean (AUC) = 0.7 (-0.4,1.7) mm Hg
140
Atenolol
Amlodipine
135
133.9
133.2
P=.07
130
mm Hg
125
125.5
121.2
120
P<.0001
Central SBP
Diff Mean (AUC) = 4.3 (3.3, 5.4) mm Hg
115
0.5 1
1.5 2
2.5 3
3.5 4
4.5 5
5.5 6
AUC
Time (Years)
Atenolol
Amlodipine
Circulation. 2006;113:

14. Brachial and Central Aortic Pulse Pressure by Treatment Arm
Brachial PP
Diff Mean (AUC) = -0.9 (-1.9, 0) mm Hg
Atenolol
Amlodipine 58
56.2
55.3
P=.06 53
mm Hg 45
46.4 43
43.4
Central PP
Diff Mean (AUC) = 3 (2.1, 3.9) mm Hg
P<.0001 38
0.5 1
1.5 2
2.5 3
3.5 4
4.5 5
5.5 6
AUC
Time (Years)
Atenolol
Amlodipine
Circulation. 2006;113:

15. Augmentation Index (%) by Treatment Arm40
Atenolol
Amlodipine 35
31.9 30
Alx (%) 25
25.3 20
Diff Mean (AUC) = -6.5 (5.8, 7.3)%
P<.0001 15
0.5 1
1.5 2
2.5 3
3.5 4
4.5 5
5.5 6
AUC
Time (Years)
Atenolol
Amlodipine
Circulation. 2006;113:

16. Results Summary (1)
Atenolol-based therapy was associated with higher central aortic systolic pressure and higher central aortic pulse pressure, despite similar brachial pressures, when compared with amlodipine-based therapy
Central aortic outgoing pressure wave (P1 height) was lower with atenolol-based therapy vs amlodipine-based therapy
Pulse wave augmentation and the percentage of the central aortic pressure wave attributable to wave reflection was increased by atenolol-based therapy compared with amlodipine-based therapy

17. Cox Regression Analysis
Secondary Objective
To define the relationship between central aortic pressures and haemodynamic parameters with clinical outcomes
Composite Clinical Outcome
Defined post-hoc when the ASCOT endpoint rate was known
Included all cardiovascular events and procedures + development of renal impairment (ASCOT pre-specified and validated endpoints)
305 events
All endpoints included from time of randomization into ASCOT
Data analyzed blind to treatment allocation
Cautious Interpretation
Limited statistical power
Circulation. 2006;113:

18. Impact of Blood Pressure and Central Aortic Haemodynamics on Clinical Outcomes in the CAFE Study (Hazard/10 mm Hg)
Updated Cox proportional hazard model for the composite endpoint, unadjusted
Factor X2 P HR CI
Peripheral PP
21.0
<.0001
1.21
Central PP
17.8
1.20
Augmentation
7.10
.008
1.22
P1 height
19.0
1.37
Updated Cox proportional hazard model for the composite endpoint, adjusted for baseline variables
Factor X2 P HR CI
Central PP
3.91
.048
1.11
Circulation. 2006;113:

19. CAFE Study Conclusions (1)
Despite similar brachial systolic blood pressure, amlodipine ± perindopril-based treatment was more effective than atenolol ± thiazide-based treatment at lowering central aortic systolic blood pressure and central aortic pulse pressure
Brachial blood pressure is not always a perfect surrogate for the effects of drug therapy on central aortic pressures

20. CAFE Study Conclusions (2)
Brachial blood pressure overestimated the haemodynamic benefit of atenolol ± thiazide-based treatment and underestimated the benefit of amlodipine ± perindopril-based treatment on central aortic pressures and haemodynamics
Central aortic pressure may be an important independent determinant of clinical outcomes
Results of the CAFE study suggest that the “central aortic blood pressure hypothesis” is a plausible mechanism to explain the better clinical outcomes for hypertensive patients treated with amlodipine ± perindopril-based therapy in ASCOT

21. The CAFE Study Investigators
CAFE Investigators and CAFE Study Centers
University Hospitals of Leicester Leicester Royal Infirmary, Leicester, UK
B. Williams, P.S. Lacy, H. Thurston, D. O’Brien, P. Swales, S. Nanayakkara, A. Stanley, K. Edwards, W. Gamble, V. Garratt, J. Harris, A. Kirkham, Y. Revell-Smith, L. Bernhardt
St. Mary’s Hospital, Paddington, London, UK
S. McG Thom, A. Whitehouse, A. Hughes, J. Macduff, S. Leech, L. Kinsley, O. Trainor, Y. Chim, A. Jack, S. Murphy, R. Baruah, F. Harrison, R. Fernandez, A. Strain, M. Liboro
The Beaumont Hospital, Dublin, Ireland
A. Stanton, E. O’Brien, E. Dolan, D. Farrell, O.B. Gallagher, S. Lyons, G. McCarthy
Manchester Royal Infirmary, Manchester, UK
K. Cruickshank, S. Dean, J. Dunkerley, M. Banerjee, M. Holland, M. Hart, M. Cullen, L. Hardstaff, J. Reynolds, J. Collins, K. Peters, M. Luckson
St. Bartholomew’s Hospital, London, UK
D. Collier, M. Caulfield, C. Waleczko, G. Salahi-Ali, J. Sheil, B. Scott, S. Wilson, C. David, H. Fok