Presentation on theme: "Accomplish Update: Fixed Dose RAAS Blocker and CCB in Prevention of Endpoints in the Treatment of Hypertension Prof. Sverre E. Kjeldsen, MD, PhD Past-President."— Presentation transcript:
Accomplish Update: Fixed Dose RAAS Blocker and CCB in Prevention of Endpoints in the Treatment of Hypertension Prof. Sverre E. Kjeldsen, MD, PhD Past-President European Society of Hypertension Department of Cardiology, Ullevaal University Hospital, Oslo, Norway, and Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, U.S.A. The 4th International Conference FIXED COMBINATION, Paris, December 3, 2011
Duke Clinical Research Institute/ Brigham and Women’s Hospital Marc A. Pfeffer Scott D. Solomon Kenneth Mahaffey Kenneth Jamerson Eric Velazquez Victor Shi, Novartis Jitendra Gupte, Novartis CentralClinicalLabs Henry R. Black, Chair Lloyd Fisher, Ph.D., Statistician Suzanne Oparil, M.D., Member Stevo Julius, M.D., Sc.D., Member Lars H. Lindholm, Member Novartis Trial Team Investigational Sites Novartis Vendors ACCOMPLISH Organizational Structure Operations Committee DSMB Kenneth Jamerson, Chair George L. Bakris Björn Dahlöf Bertram Pitt Eric Velazquez Michael A. Weber Steering Committee Sverre Kjeldsen Jan Östergren Jaakko Tuomilehto Hans Ibsen William C. Cushman Richard Devereux Brent Egan Barry M. Massie Shawna D. Nesbitt Elizabeth Ofili Vasilios Papademetriou Matthew R. Weir Jackson T. Wright, Jr. Independent Statistician Tom Greene Endpoint Committee Endpoint Coordinating Center Executive Committee
ACCOMPLISH: Design Jamerson KA et al. Am J Hypertens. 2003;16(part2)193A *Beta blockers; alpha blockers; clonidine; (loop diuretics). 14 Days Day 1 Month 1 Month 2 Year 5 Screening Amlodipine 5 mg + benazepril 20 mg Randomization Benazepril 40 mg + HCTZ 12.5 mg Benazepril 40 mg + HCTZ 25 mg Free add-on antihypertensive agents* Month 3 Free add-on antihypertensive agents* Amlodipine 5 mg + benazepril 40 mg Amlodipine 10 + benazepril 40 mg Benazepril 20 mg + HCTZ 12.5 mg Titrated to achieve BP<140/90 mmHg; <130/80 mmHg in patients with diabetes or renal insufficiency
Targeted Population for Recruitment into the ACCOMPLISH Study Men or women age ≥ 55 years SBP ≥ 160 mmHg or currently on antihypertensive therapy Evidence of cardiovascular or renal disease or target organ damage Accomplish randomized 3333 Nordic patients, 8067 American including 1361 African American patients, 6921 patients with diabetes (60%) and 680 patients with Chronic Renal Disease
Systolic Blood Pressure Over Time mm Hg Month 57315387520649994804428525201045 57095377515449804831428625941075 Patients ACEI / HCTZ N=5733 CCB / ACEI N=5713 *Mean values are taken at 30 months F/U visit 129.3 mmHg 130mmHg Difference of 0.7 mmHg p<0.05* DBP: 71.1DBP: 72.8
Baseline Control Rates 37.2 37.9 ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy ACEI / HCTZ N=5733 Control rate (%) CCB / ACEI N=5713 10 20 30 40 50 60 70 80 90 78.5 81.7 P<0.001 at 30 months follow-up Control defined as <140/90 mmHg
Kaplan Meier for Primary Endpoint Cumulative event rate Jamerson K et al. New Engl J Med 2008; 359: 2417-28. 20% Risk Reduction Time to 1 st CV morbidity/mortality (days) p = 0 ACEI / HCTZ CCB / ACEI 650 526.0002 HR (95% CI): 0.80 (0.72, 0.90)
0.51.0 2.0 Primary Endpoint and Components Composite CV mortality/morbidity Cardiovascular mortality Non-fatal MI Non-fatal stroke Hospitalization for unstable angina Coronary revascularization procedure Resuscitated sudden death Incidence of adjudicated primary endpoints, based upon cut-off analysis date 3/24/2008 (Intent-to-treat population) Risk Ratio (95%) Favors CCB / ACEI Favors ACEI / HCTZ 0.80 (0.72–0.90) 0.81 (0.62-1.06) 0.81 (0.63-1.05) 0.87 (0.67-1.13) 0.74 (0.49-1.11) 0.85 (0.74-0.99) 1.75 (0.73-4.17) Jamerson K et al. New Engl J Med 2008; 359: 2417-28.
Primary and Other Endpoints Composite CV mortality/morbidity Primary w/o revascularization Hard CV endpoint (CV death, non-fatal MI, non-fatal stroke) All cause mortality Incidence of adjudicated primary endpoints, based upon cut-off analysis date 3/24/2008 (Intent-to-treat population) Risk Ratio (95%) 0.80 (0.72–0.90) 0.79 (0.68–0.92) 0.80 (0.68–0.94) 0.90 (0.75–1.08) 0.51.0 2.0 Favors CCB / ACEI Favors ACEI / HCTZ Jamerson K et al. New Engl J Med 2008; 359: 2417-28.
24-Hour Mean Ambulatory SBP at Year 2 145 140 135 130 125 120 115 110 Mean ambulatory SBP (mmHg) 123456789101112131415161718192021222324 Benazepril/amlodipine N=288 Benazepril/HCTZ N=285 Mean difference 1.6 mmHg p=0.128 Jamerson K et al. Hypertension 2011; 57: 174-179. Hour 10 AM (Mean difference in 24 hour DBP = 0.3 mmHg, p=0.7)
ACCOMPLISH: Progression of chronic kidney disease (doubling of se-creatinine or ESRD) for the ITT population Bakris GL et.al. Lancet 2010, Feb 18th
Changes in blood pressure throughout the trial in patients with chronic kidney disease Bakris GL et.al. Lancet 2010, Feb 18th N=680
Blood Pressure in Pts. With and Without Diabetes Weber M, Bakris G, Kjeldsen SE et al. JACC 2010; 56: 77-85.
Primary Event in Pts. With and Without Diabetes Weber M, Bakris G, Kjeldsen SE et al. JACC 2010; 56: 77-85.
ACCOMPLISH Main Findings Fixed-dose forced titration of two drug combinations (ACEI/CCB or ACEI/HCTZ) achieved BP control in 80% of participants – the highest control rate ever seen in a large outcome trial in hypertension ACEI/CCB combination reduced primary CV endpoint by 20% The ambulatory BP substudy confirmed same BP control in ACEI/CCB and ACEI/HCTZ arms Treatment with ACEI/CCB reduced the secondary renal endpoint (doubling of se-creatinine or ESRD) Benefits of ACEI/CCB combination was homogenous through main subgroups of non-diabetics, diabetics and high-risk diabetics