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The Conduit Artery Functional Evaluation (CAFE) Study Principal Results

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.

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The Conduit Artery Functional Evaluation (CAFE) Study Principal Results

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  1. The Conduit Artery Functional Evaluation (CAFE) StudyPrincipal 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

  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;113:1213-1225

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

  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;113:1213-1225

  9. Baseline Demographics (1) Circulation. 2006;113:1213-1225

  10. Baseline Demographics (2) Circulation. 2006;113:1213-1225

  11. Treatment Algorithm Further treatment to achieve blood-pressure goal outlined at http://www.ascotstudy.org. All drugs given orally. Circulation. 2006;113:1213-1225

  12. Haemodynamic Data Data: Area under Curve ± 95% CI Circulation. 2006;113:1213-1225

  13. Brachial and Central Aortic Systolic Blood Pressure (± 95% CI) Brachial SBP Diff Mean (AUC) = 0.7 (-0.4,1.7) mm Hg Atenolol 140 Amlodipine 135 133.9 133.2 P=.07 130 mm Hg 125.5 125 121.2 120 P<.0001 Central SBP Diff Mean (AUC) = 4.3 (3.3, 5.4) mm Hg 115 AUC 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 Time (Years) Atenolol 86 243 324 356 445 372 462 270 339 128 85 1031 Amlodipine 88 248 329 369 475 406 508 278 390 126 101 1042 Circulation. 2006;113:1213-1225

  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 AUC 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 Time (Years) Atenolol 86 243 324 356 445 372 462 270 339 128 85 1031 Amlodipine 88 248 329 369 475 406 508 278 390 126 101 1042 Circulation. 2006;113:1213-1225

  15. Augmentation Index (%) by Treatment Arm 40 Atenolol Amlodipine 35 31.9 30 Alx (%) 25 25.3 20 Diff Mean (AUC) = -6.5 (5.8, 7.3)% P<.0001 15 AUC 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 Time (Years) Atenolol 86 243 324 356 445 372 462 270 339 128 85 1031 Amlodipine 88 248 329 369 475 406 508 278 390 126 101 1042 Circulation. 2006;113:1213-1225

  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;113:1213-1225

  18. Impact of Blood Pressure and Central Aortic Haemodynamics on Clinical Outcomes in the CAFE Study (Hazard/10 mm Hg) Circulation. 2006;113:1213-1225

  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

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