The Conduit Artery Functional Evaluation (CAFE) Study Principal

The Conduit Artery Functional Evaluation (CAFE) Study Principal

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 ORourke For the ASCOT Investigators 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 University Department of Cardiovascular Sciences University of Leicester, Leicester, UK 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 Stephens Green, Dublin, Ireland Dr David Collier Department of Clinical Pharmacology, William Harvey Research Institute, Barts & The London, Queen Marys School of Medicine & Dentistry, London, UK Professor Simon McG Thom Clinical Pharmacology and Therapeutics St. Marys Hospital Imperial College London London, UK Professor Herbert Thurston University Department of Cardiovascular Sciences

University of Leicester, Leicester, UK Study Advisor Professor Michael ORourke 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 ASCOT Sub-Study Committee Liaison: Prof. Eoin OBrien, Prof. Mark Caulfield For the CAFE Investigators and ASCOT Investigators 2 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 pressurelowering drugs may differentially influence central aortic blood pressures 3 Background (2) In clinical trials comparing different blood pressure loweringdrugs, 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) 4 CAFE Hypothesis Primary Objective The different blood pressurelowering 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 ORourke M. J Hum Hypertens. 2001;15(suppl 1):S69-S73. 5 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;113:1213-1225 6 Pulse Wave Analysis Brachial Blood Pressure

Sensor Artery Bone 140 Transfer function 70 140 70 Radial Central Aortic 7 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 intentionto-treat basis 1038 complete information (997 alive, 41 dead) 1031 assessed on an intentionto treat basis 1030 complete information (989 alive, 41 dead) Circulation. 2006;113:1213-1225 8 Baseline Demographics (1) CAFE Atenolol-based n=1031 Women Age (years) White Current smoker SBP mm Hg 189 (18.3%) 62.6 (8.3) 886 (85.9%) 251 (24.3%) 159.9 (16.6) ASCOT Amlodipinebased n=1042 208 (20%) 62.9 (8.2) 892 (85.6%) 267 (25.6%) 161 (18.4) Atenolol-based n=9639 2257 (23.5%) 63.0 (8.5) 9170 (95.3%)

3109 (32.3%) Amlodipinebased n=9618 2258 (23.4%) 63.0 (8.5) 9187 (95.3%) 3168 (32.9%) 163.9 (18) 164.1 (18.1) DBP (mm Hg) 92.4 (9.6) 92.6 (9.8) 94.5 (10.4) Heart rate (bpm) 71.8 (12.3) 71.2 (12.4) 71.8 (12.6) 29 (4.5) 170.7 (8.7) 224.3 (38.7) 29.1 (4.7) 170.2 (9.4) 224.3 (42.5) 28.7 (4.5) NA 228.2 (42.5) BMI (kg/m2)

Height (cm) Total cholesterol (mg/dL) (10.4) (12.7) 94.8 71.9 28.7 (4.6) NA 228.2 (42.5) LDL-cholesterol (mg/dL) 143.1 (34.8) Circulation. 2006;113:1213-1225 143.1 (34.8) 146.9 (38.7) 146.9 (38.7) 9 Baseline Demographics (2) CAFE AmlodipineAtenolol-based based n=1031 n=1042 ASCOT AtenololAmlodipinebased based n=9639 n=9618 Medical history

Prior stroke/TIA Diabetes LVH (echo or ECG) Peripheral vascular disease Other relevant CV disease Mean (SD) # risk factors 76 (7.4%) 252 (24.4%) 237 (23%) 61 (5.9%) 22 (2.1%) 3.7 (0.9) 101(9.7%) 251 (24.4%) 256 (24.6%) 59 (5.7%) 27 (2.6%) 3.7 (0.9) 1063 (11.1%) 1050 (10.9%) 2578 (26.8%) 2567 (26.6%) 2076 (21.6%) 2091 (21.7%) 613 (6.4%) 586 (6.1%) 486 (5.1%) 533 (5.5) 3.7 3.7 (0.9) (0.9) Drug therapy BP treatment naive Lipid-lowering therapy Aspirin use 109 (10.6%) 120 (11.6%) 244 (23.7%) 100 (9.6%) 120 (11.5%)

274 (26.3%) 1825 (19%) 1841 (19.1%) 1004 (10.4%) 1046 (10.9%) 1837 (19.1%) 1851 (19.2%) Circulation. 2006;113:1213-1225 10 Treatment Algorithm Step 1 -Blocker Based Regimen Calcium Channel Blocker Regimen 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 25 mg Step 5

Amlodipine 10 mg + perindopril 8 mg (2x4 mg) + doxazosin gastrointestinal transport system 4 mg Atenolol 100 mg + bendroflumethiazide K 25 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 25 mg + doxazosin gastrointestinal transport system 8 mg Further treatment to achieve blood-pressure goal outlined at http://www.ascotstudy.org. All drugs given orally. Circulation. 2006;113:1213-1225 11 Haemodynamic Data Parameter Atenolol Amlodipine Difference (AtenololAmlodipine) 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) <.0001 Statistics t-test (P) Data: Area under Curve 95% CI Circulation. 2006;113:1213-1225 12 Brachial and Central Aortic Systolic Blood Pressure ( 95% CI) Brachial SBP Diff Mean (AUC) = 0.7 (-0.4,1.7) mm Hg Atenolol Amlodipine 140 mm Hg 135 130 133.9 133.2 P=.07 125 125.5 121.2 120 P<.0001 Central SBP Diff Mean (AUC) = 4.3 (3.3, 5.4) mm Hg

115 0 Atenolol Amlodipine 0.5 1 1.5 86 88 243 248 2 2.5 3 3.5 4 Time (Years) 4.5 324 356 445 372 462 270 329 369 475 406 508 278 Circulation. 2006;113:1213-1225 6 AUC 339 128 85

390 126 101 1031 1042 5 5.5 13 Brachial and Central Aortic Pulse Pressure by Treatment Arm Brachial PP Diff Mean (AUC) = -0.9 (-1.9, 0) mm Hg Atenolol Amlodipine mm Hg 58 56.2 55.3 P=.06 53 45 46.4 43 43.4 Central PP Diff Mean (AUC) = 3 (2.1, 3.9) mm Hg 38 0 Atenolol Amlodipine

0.5 1 1.5 86 88 243 248 2 2.5 3 3.5 P<.0001 4 Time (Years) 4.5 324 356 445 372 462 270 329 369 475 406 508 278 Circulation. 2006;113:1213-1225 5 5.5 6 339 128 85 390 126 101 AUC

1031 1042 14 Augmentation Index (%) by Treatment Arm 40 Atenolol Amlodipine 35 Alx (%) 31.9 30 25 25.3 20 Diff Mean (AUC) = -6.5 (5.8, 7.3)% P<.0001 15 0 Atenolol Amlodipine 0.5 1 1.5 86 88 243 248 2

2.5 3 3.5 4 Time (Years) 4.5 324 356 445 372 462 270 329 369 475 406 508 278 Circulation. 2006;113:1213-1225 6 AUC 339 128 85 390 126 101 1031 1042 5 5.5 15 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 16 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;113:1213-1225 17 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 1.12-1.30 Central PP 17.8 <.0001 1.20 1.11-1.30 Augmentation 7.10 .008 1.22 1.06-1.40 P1 height 19.0 <.0001 1.37 1.20-1.54 Updated Cox proportional hazard model for the composite endpoint, adjusted for baseline variables

Factor Central PP X2 P HR CI 3.91 .048 1.11 1.00-1.21 Circulation. 2006;113:1213-1225 18 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 19 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 20 The CAFE Study Investigators CAFE Investigators and CAFE Study Centers University Hospitals of Leicester Leicester The Beaumont Hospital, Dublin, Ireland Royal Infirmary, Leicester, UK A. Stanton, E. OBrien, E. Dolan, D. Farrell, B. Williams, P.S. Lacy, H. Thurston, O.B. Gallagher, S. Lyons, G. McCarthy D. OBrien, P. Swales, S. Nanayakkara, Manchester Royal Infirmary, A. Stanley, K. Edwards, W. Gamble, Manchester, UK V. Garratt, J. Harris, A. Kirkham, K. Cruickshank, S. Dean, J. Dunkerley, Y. Revell-Smith, L. Bernhardt M. Banerjee, M. Holland, M. Hart, M. Cullen, St. Marys Hospital, Paddington, L. Hardstaff, J. Reynolds, J. Collins, London, UK K. Peters, M. Luckson S. McG Thom, A. Whitehouse, A. Hughes, St. Bartholomews Hospital, London, UK J. Macduff, S. Leech, L. Kinsley, O. Trainor, D. Collier, M. Caulfield, C. Waleczko, Y. Chim, A. Jack, S. Murphy, R. Baruah, G. Salahi-Ali, J. Sheil, B. Scott, S. Wilson, F. Harrison, R. Fernandez, A. Strain, C. David, H. Fok M. Liboro 21

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