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