Slide 1 RENAAL Reduction of Endpoints in NIDDM with the A II Antagonist Losartan An investigator-initiated, multicenter, double-blind, randomized, placebo-controlled

Slide 1

RENAALRENAALRReduction of eduction of EEndpoints in ndpoints in NNIDDM with IDDM with

the the AAIIII AAntagonist ntagonist LLosartanosartan

An investigator-initiated, multicenter, double-blind, randomized, placebo-controlled study to evaluate the renal protective

effects of losartan in patients with Type 2 diabetes and nephropathy

1513 Patients; 250 Centers; 28 Countries

• Steering Committee Chair B. M. Brenner, MD

• Data and Safety Monitoring Committee Chair C. E. Mogensen, MD

• Clinical Endpoint Adjudication Committee Chair S. Haffner, MD

• Coordinating Center: Merck Research Labs Study Director S. Shahinfar, MD

Data from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334; Brenner BM et al N Engl J Med 2001;345(12):861-869.

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RENAAL RENAAL Primary HypothesisPrimary Hypothesis

• Long-term treatment with losartan versus placebo (alone or in combination with conventional antihypertensive therapy*) in Type 2 diabetic patients with nephropathy will increase the time to first event and decrease the incidence of doubling of sCr, ESRD, or death

*Excluding ACE inhibitors and other AII antagonists

sCr=serum creatinine

Data from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334.

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Slide 3

• Losartan compared to placebo (alone or in combination with conventional antihypertensive therapy*) in patients with Type 2 diabetes and nephropathy will

– Increase the time to first event and decrease the incidence of cardiovascular morbidity/mortality

– Reduce proteinuria

– Decrease the rate of progression of renal disease

*Excluding ACE inhibitors and other AII antagonists


RENAAL RENAAL Secondary HypothesisSecondary Hypothesis

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RENAAL RENAAL Study DesignStudy Design

qd=once daily

*CT=conventional therapy: Open-label calcium-channel blocker, diuretic, beta blocker, alpha blocker, or centrally acting agents.


4 wk

Losartan 100 mg qd(+CT)

Maintain conventional antihypertensive therapy (CT)*

(excluding ACE inhibitors, AII antagonists)

Losartan 100 mg qd (+CT)

Placebo(+CT)

Goal trough BP:<140/<90 mmHg

n=1513

Placebo (+CT)

Losartan 50 mg qd(+CT)

Placebo(+CT)

8 wk 6 wk

Mean follow-up 3.4 years

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RENAALRENAAL Inclusion/Exclusion Criteria Inclusion/Exclusion Criteria

Inclusion criteriaInclusion criteria

Type 2 diabetes

Age 31–70 years

Proteinuria:urine albumin:cr >300 mg/g or 24-hr protein >500 mg

sCr: 1.3–3.0 mg/dl, 115–265 µmol/L*

Exclusion criteria

Type 1 diabetes

Known non-diabetic renal disease or renal artery stenosis

Recent history of MI, CABG, PTCA, CVA, TIA

History of HF

HbA1c >12%

CABG=coronary artery bypass graft; PTCA=percutaneous transluminal coronary angioplasty; CVA=cerebral vascular accident; TIA=transient ischemic attacks

*Lower limit 1.5 mg/dl (133 µmol/L) in male patients >60 kg


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Europe19%

Latin America18%

North America 46%

Asia17%


RENAAL RENAAL Enrollment by RegionEnrollment by Region

N=1513N=1513

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Losartan (+CT) Placebo (+CT)(n=751) (n=762)

Age, years 60 60Male, % 62 65Female, % 38 35Race, % Asian 16 18 Black 17 14 Caucasian 48 50 Hispanic 19 18 Other 2 1Systolic BP, mmHg 152 153Diastolic BP, mmHg 82 82BMI, kg/m2 30 29


RENAAL RENAAL Baseline CharacteristicsBaseline Characteristics

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RENAAL RENAAL Primary Composite Endpoint and ComponentsPrimary Composite Endpoint and Components

Losartan (+CT) Placebo (+CT) Composite (n=751) (n=762) % Risk and components n (%) n (%) p Value reduction 95% CI

DsCr, ESRD, Death 327 (43.5) 359 (47.1) 0.02 16 (2, 28)

DsCr 162 (21.6) 198 (26.0) 0.006 25 (8, 39)

ESRD 147 (19.6) 194 (25.5) 0.002 28 (11, 42)

Death 158 (21.0) 155 (20.3) 0.88 –2 (–27, 19)

ESRD or death 255 (34.0) 300 (39.4) 0.01 20 (5, 32)

DsCr=doubling of serum creatinine; CI=confidence interval

Data from Brenner BM et al N Engl J Med 2001;345(12):861-869.

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ESRD

Months

% w

ith

ev

ent

0 12 24 36 480

10

20

30

RR: 28%p=0.002

ESRD or Death

Months

% w

ith

ev

ent

sCr=serum creatinine; RR=risk reduction


RENAAL Primary Components

Doubling of sCr

Months

% w

ith

ev

ent

RR: 25% p=0.006

Placebo (+CT) 762 689 554 295 36 Losartan (+CT) 751 692 583 329 52

RR: 20%p=0.010


0 12 24 36 48

0

10

20

30

40

50

0 12 24 36 480

10

20

30


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RENAALRENAALPrimary Composite EndpointPrimary Composite Endpoint

Doubling of sCr / ESRD / DeathDoubling of sCr / ESRD / Death

Months

% w

ith

eve

nt

RR: 16%p=0.02

Months0 12 24 36 48

0

10

20

30

40

50

RR: 22%p=0.008

Placebo (+CT) 762 689 554 295 36 760 584 431 214 24 Losartan (+CT) 751 692 583 329 52 746 612 479 263 36

ITT analysis Per-protocol analysis

Data from Brenner BM et al N Engl J Med 2001;345(12):861-869

0 12 24 36 480

10

20

30

40

50

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Baseline Year 1 Year 2 Study End

Systolic/diastolicLosartan (+CT) 152/82 146/78 143/77 140/74Placebo (+CT) 153/82 150/80 144/77 142/74

Mean arterial pressureLosartan (+CT) 105.5 100.9 99.1 95.9Placebo (+CT) 106.0 103.1 99.7 96.8

Pulse pressureLosartan (+CT) 69.4 67.8 66.2 66.7Placebo (+CT) 70.8 69.8 67.1 67.4


RENAALRENAALBP (mmHg)BP (mmHg)

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RR p Value RR p Value RR p Value

Unadjusted 16% 0.02 28% 0.002 20% 0.01Adjusted 15% 0.03 26% 0.007 19% 0.016

DsCr/ESRD/Death ESRD ESRD/Death

RENAAL RENAAL Risk Reduction for Primary Composite Endpoint and Risk Reduction for Primary Composite Endpoint and

Components After Adjusting for Mean Arterial PressureComponents After Adjusting for Mean Arterial Pressure


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RENAALRENAALDose of Losartan Dose of Losartan

• The daily dose of losartan ranged from 50–100 mg

100 mg qd

Losartan*n=751

%

71

*Patients who took the dose more than 50% of the time.


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RENAALRENAALConcurrent Antihypertensive MedicationsConcurrent Antihypertensive Medications

Losartan PlaceboTherapeutic Class (n=751) (n=762)

Calcium-channel blocker, % 77.9 81.1 Dihydropyridine, % 60.7 63.9

Diuretic, % 83.8 84.0

Alpha blocker, % 40.2 45.7

Beta blocker, % 34.1 36.7

Centrally acting agents ,% 18.0 21.7


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RENAAL RENAAL Secondary Composite EndpointSecondary Composite Endpoint

and Componentsand Components

Losartan (+CT) Placebo (+CT) Composite (n=751) (n=762) % Risk and components n (%) n (%) p Value reduction 95% CI

CV morbidity/mortality 247 (32.9) 268 (35.2) 0.255 10 (–8, 24)

CV death 90 (12.0) 79 (10.4) 0.455 –12 (–52, 17)

HF 89 (11.9) 127 (16.7) 0.005 32 (11, 48)

MI 50 (6.7) 68 (8.9) 0.079 28 (–4, 50)

Unstable angina 42 (5.6) 41 (5.4) 0.881 –3 (–59, 33)

Stroke 47 (6.3) 50 (6.6) 0.787 5 (–41, 36)

Revascularization 69 (9.2) 60 (7.9) 0.331 –19 (–68, 16)

CV=cardiovascular


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RENAALRENAALFirst Hospitalization for Heart FailureFirst Hospitalization for Heart Failure

0 12 24 36 48

Months

0

5

10

15

20

% w

ith

eve

nt

Risk reduction: 32%p=0.005

Placebo (+CT) 762 685 616 375 53Losartan (+CT) 751 701 637 388 74


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0 12 24 36 48Months

Med

ian

% c

han

ge

–60

–40

–20

0

20

40

35% Overall reductionp<0.001

RENAALRENAALChange from Baseline in ProteinuriaChange from Baseline in Proteinuria

Proteinuria measured as the urine albumin:creatinine ratio from a first morning void.


Placebo (+CT) 762 632 529 390 130Losartan (+CT) 751 661 558 438 167

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RENAALRENAALRate of Progression of Renal Disease Rate of Progression of Renal Disease

(median 1/sCr slope)(median 1/sCr slope)

Losartan (+CT) Placebo (+CT)0

–0.02

–0.04

–0.06

–0.08

dl/m

g/y

r

–0.056

–0.069

p=0.0118% reduction


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Slide 19

Public Health and Economic Implications Public Health and Economic Implications of RENAAL (US)of RENAAL (US)

• For diabetic patients at risk over a 3.5-year period, it is estimated that– Addition of losartan to the treatment regimens of 100 patients

with Type 2 diabetes and nephropathy would be expected to lead to a reduction of 6.3 cases of ESRD

– In RENAAL, losartan reduced ESRD days by 31%• Reduction in days with ESRD saves $5144 (p=0.003) per treated patient at 3.5 years and

$7058 (p=0.002) per patient over 4 years• After accounting for costs of losartan, reduction in ESRD resulted

in net savings of $3522 per patient over 3.5 years (95% CI: $143–$6900) and $5298 (95% CI: $954–$9643) per patient over 4 years

Costs are reported in 2001 US dollars.

Data from Herman WH et al Diabetes Care 2003;26(3):683-687.

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Public Health and Economic Implications Public Health and Economic Implications of RENAAL (EU)of RENAAL (EU)

• Extrapolating the addition of losartan to the treatment regimen of patients with Type 2 diabetes and proteinuria in the EU– 44,092 cases of ESRD averted (95% CI: 11,898–76,286)

after 3.5 years– 64,383 years with ESRD averted (95% CI: 20,886–107,879)

after 3.5 years– Reduction in ESRD-related costs of €2.6 billion after 3.5 years,

increasing to €3.6 billion after 4 years

Costs based on ESRD costs in Germany in 1999.

Data from Gerth WC et al Kidney Int 2002;62(suppl 82) S68-S72.

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RENAAL RENAAL Summary (Summary (II))

• In patients with Type 2 diabetes and nephropathy– Losartan delayed onset of the primary composite

endpoint (DsCr/ESRD/Death) and delayed progression to ESRD

– Losartan reduced proteinuria and the rate of decline in renal function (assessed by the reciprocal of sCr concentration)

– Losartan reduced the incidence of hospitalization for heart failure

– These benefits were largely independent of BP


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RENAAL RENAAL Summary (Summary (IIII) )

• In patients with Type 2 diabetes and nephropathy– Losartan and placebo, added to CT, showed no

significant difference in all-cause mortality, MI, stroke, revascularization, hospitalizations for unstable angina, and death due to CV disease

– Losartan was generally well tolerated in this patient population


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RENAALRENAALConclusionsConclusions

• Losartan confers significant benefits on renal outcomes in Type 2 diabetic patients with nephropathy

• Losartan therapy results in a significant reduction in hospitalizations for heart failure

• These benefits of losartan are largely independent of achieved BP

• Losartan is generally well tolerated


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Slide 24

• RENAAL results show that losartan + CT

– Provided excellent tolerability

– Provided proven renal protection and cardioprotective benefit 28% risk reduction in ESRD 32% risk reduction in incidence of first hospitalization

for heart failure 35% reduction in proteinuria

• Analysis of the public health implications of RENAAL shows potential of losartan for substantial healthcare savings

RENAAL RENAAL Losartan Renal Protection StudyLosartan Renal Protection Study

Data from Brenner BM et al N Engl J Med 2001;345(12):861-869; Herman WH et al Diabetes Care 2003;26(3):683-687;Gerth WC et al Kidney Int 2002;62(suppl 82):S68-S72.

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Why Is RENAAL Relevant to the Why Is RENAAL Relevant to the Treatment of Hypertension?Treatment of Hypertension?

• High BP causes increased risk for cardiac, renal and cerebrovascular events (MI, HF, ESRD, stroke)

• RENAAL provided strong evidence of a need to block the pathological effects of angiotensin II beyond BP

• RENAAL demonstrated that specific AII blockade with losartan in hypertensive patients with Type 2 diabetes and nephropathy helps control the course of disease and delays ESRD

• RENAAL demonstrated that losartan provides renal protection and a cardioprotective benefit

Data from Whelton PK et al J Hypertens 1992;10(suppl 7):S77-S84; MacMahon S et al Lancet 1990;335:765-774; Kannel WB JAMA 1996;274(24):1571-1576; Klag MJ et al N Engl J Med 1996;334:13-18; Brenner BM et al N Engl J Med 2001;345(12):861-869.

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Slide 26

ReferencesReferences

• Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4): 328-334

• Brenner BM et al N Engl J Med 2001;345(12):861-869• Herman WH et al Diabetes Care 2003;26(3):683-687• Gerth WC et al Kidney Int 2002;62(suppl 82):S68-S72• Whelton PK et al J Hypertens 1992;10(suppl 7):S77-S84• MacMahon S et al Lancet 1990;335:765-774• Kannel WB JAMA 1996;274(24):1571-1576• Klag MJ et al N Engl J Med 1996;334:13-18

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Data dep AIFA 23/12/2009

Copyright 2003, 2009 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehaouse Station, NJ, U.S.A.

All rights reserved

Prima della prescrizione, consultare il Riassunto delle caratteristiche del prodotto.

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CARD-1071592-0000-CZR-SS-02/2015

Documents

Slide 1 RENAAL Reduction of Endpoints in NIDDM with the A II Antagonist Losartan An investigator-initiated, multicenter, double-blind, randomized, placebo-controlled