Prof. Sverre E. Kjeldsen, MD, PhD Past-President European Society of Hypertension
description
Transcript of Prof. Sverre E. Kjeldsen, MD, PhD Past-President European Society of Hypertension
Accomplish Update: Fixed Dose RAAS Blocker and CCB in Prevention of Endpoints in the
Treatment of Hypertension
Prof. Sverre E. Kjeldsen, MD, PhDPast-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 Duke Clinical Clinical
ResearchResearchInstitute/Institute/Brigham Brigham
and and Women’s Women’s HospitalHospital
Marc A. PfefferMarc A. PfefferScott D. SolomonScott D. SolomonKenneth MahaffeyKenneth Mahaffey
Kenneth JamersonKenneth JamersonEric VelazquezEric Velazquez
Victor Shi, NovartisVictor Shi, NovartisJitendra Gupte, NovartisJitendra Gupte, Novartis
CentralCentralClinicalClinical
LabsLabs
Henry R. Black, Henry R. Black, ChairChairLloyd Fisher, Ph.D., Lloyd Fisher, Ph.D.,
StatisticianStatisticianSuzanne Oparil, M.D., Suzanne Oparil, M.D., MemberMember
Stevo Julius, M.D., Sc.D., Stevo Julius, M.D., Sc.D., MemberMember
Lars H. Lindholm, Lars H. Lindholm, MemberMember
Novartis Novartis Trial TeamTrial Team
Investigational SitesInvestigational Sites
Novartis Novartis VendorsVendors
ACCOMPLISH Organizational StructureOperations CommitteeDSMB
Kenneth Jamerson, Kenneth Jamerson, ChairChairGeorge L. BakrisGeorge L. Bakris
Björn DahlöfBjörn DahlöfBertram PittBertram Pitt
Eric VelazquezEric VelazquezMichael A. WeberMichael A. Weber
SteeringCommittee
Sverre KjeldsenSverre KjeldsenJan ÖstergrenJan Östergren
Jaakko TuomilehtoJaakko TuomilehtoHans IbsenHans Ibsen
William C. CushmanWilliam C. CushmanRichard DevereuxRichard Devereux
Brent EganBrent EganBarry M. MassieBarry M. Massie
Shawna D. NesbittShawna D. NesbittElizabeth OfiliElizabeth Ofili
Vasilios PapademetriouVasilios PapademetriouMatthew R. WeirMatthew R. Weir
Jackson T. Wright, Jr.Jackson T. Wright, Jr.
Independent Statistician
Tom GreeneTom Greene
EndpointCommittee
Endpoint Coordinatin
gCenter
Executive Committee
ACCOMPLISH: DesignACCOMPLISH: Design
Jamerson KA et al. Am J Hypertens. 2003;16(part2)193A
*Beta blockers; alpha blockers; clonidine; (loop diuretics).*Beta blockers; alpha blockers; clonidine; (loop diuretics).
14 Days14 Days Day 1Day 1 Month 1Month 1 Month 2Month 2 Year 5Year 5
ScreeningScreening
Amlodipine 5 mg +Amlodipine 5 mg +benazepril 20 mgbenazepril 20 mg
Ran
dom
izati
on
Ran
dom
izati
on
Benazepril 40 mg Benazepril 40 mg + HCTZ 12.5 mg+ HCTZ 12.5 mg
Benazepril 40 mg Benazepril 40 mg + HCTZ 25 mg+ HCTZ 25 mg
Free add-on Free add-on antihypertensivantihypertensive agents*e agents*
Month 3Month 3
Free add-on Free add-on antihypertensivantihypertensive agents*e agents*
Amlodipine 5 mg +Amlodipine 5 mg +benazepril 40 mgbenazepril 40 mg
Amlodipine 10 +Amlodipine 10 +benazepril 40 mgbenazepril 40 mg
Benazepril 20 mg Benazepril 20 mg + HCTZ 12.5 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 Targeted Population for Recruitment into the ACCOMPLISH StudyACCOMPLISH 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 TimeSystolic Blood Pressure Over Timem
m H
g
Month
5731 5387 5206 4999 4804 4285 2520 10455709 5377 5154 4980 4831 4286 2594 1075
Patients
ACEI / HCTZN=5733
CCB / ACEIN=5713
*Mean values are taken at 30 months F/U visit
129.3 mmHg
130mmHg
Difference of 0.7 mmHg p<0.05*
DBP: 71.1 DBP: 72.8
Baseline Control Rates37.2 37.9
ACCOMPLISH: Exceptional Control Rates ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapywith Initial Combination Therapy
ACEI / HCTZN=5733
Co
ntr
ol
rate
(%
)
CCB / ACEIN=5713
10
20
30
40
50
60
70
80
9078.5
81.7
P<0.001 at 30 months follow-up Control defined as <140/90 mmHg
Kaplan Meier for Primary EndpointKaplan Meier for Primary EndpointC
umul
ativ
e ev
ent
rate
Jamerson K et al. New Engl J Med 2008; 359: 2417-28.
20% Risk Reduction
Time to 1st CV morbidity/mortality (days)
p = 0
ACEI / HCTZ
CCB / ACEI650
526
.0002HR (95% CI): 0.80 (0.72, 0.90)
0.50.5 1.01.0 2.02.0
Primary Endpoint and ComponentsPrimary Endpoint and Components
Composite CV mortality/morbidityComposite CV mortality/morbidity
Cardiovascular mortalityCardiovascular mortality
Non-fatal MINon-fatal MI
Non-fatal strokeNon-fatal stroke
Hospitalization for unstable anginaHospitalization for unstable angina
Coronary revascularization procedureCoronary revascularization procedure
Resuscitated sudden deathResuscitated sudden death
Incidence of adjudicated primary endpoints, based upon cut-off analysis date 3/24/2008
(Intent-to-treat population)
Risk RatioRisk Ratio(95%)(95%)
Favors CCB / ACEI
Favors ACEI / HCTZ
0.80 (0.72–0.90)0.80 (0.72–0.90)
0.81 (0.62-1.06)0.81 (0.62-1.06)
0.81 (0.63-1.05)0.81 (0.63-1.05)
0.87 (0.67-1.13)0.87 (0.67-1.13)
0.74 (0.49-1.11)0.74 (0.49-1.11)
0.85 (0.74-0.99)0.85 (0.74-0.99)
1.75 (0.73-4.17)1.75 (0.73-4.17)
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
Mea
n am
bula
tory
SB
P (
mm
Hg)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
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.
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