Slide 1 Downloaded from www.cozaar.ae RENAAL Altering the Course of Renal Disease in Hypertensive Patients with Type 2 Diabetes and Nephropathy with the AII Antagonist Losartan
Dec 22, 2015
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RENAAL
Altering the Course of Renal Disease in Hypertensive Patients with
Type 2 Diabetes and Nephropathy with the AII Antagonist Losartan
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Angiotensin Angiotensin IIII Drives Pathology Drives Pathology in Hypertension in Hypertension
HypertensionHypertension
Vascular Dysfunction
Endothelial dysfunction
Remodeling/hypertrophy
Fibrosis
Atherosclerosis
Tissue DysfunctionCell loss
Fibrosis
Remodeling
Ischemia
Heart MI, HF
Kidney ESRD
Brain Stroke
Genetics, risk factors (diabetes, hypercholesterolemia)
Environment (diet, smoking, stress)
MI=myocardial infarction; HF=heart failure; ESRD=end-stage renal disease
Adapted from Weir MR, Dzau VJ Am J Hypertens 1999;12:205S-235S; Timmermans PB et al Pharmacol Rev 1993;45(2):205-251; and Jessup M, Brozena S N Engl J Med 2003;348:2007-2018.
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Clinical Endpoint Data for ESRD in Type 2 Clinical Endpoint Data for ESRD in Type 2 Diabetes with ACE Inhibitors Are LackingDiabetes with ACE Inhibitors Are Lacking
Endpoints StudiedACE Inhibitor Trialsin Type 2 Diabetics Total Reduction of Reduction of Reduction in Risk with >1 Year Follow-Up Sample Proteinuria GFR Decline of ESRD*
Ravid et al Ann Intern Med 1993 94 Yes YesNoLebovitz et al Kidney Int 1994 121 Yes YesNoBakris et al Kidney Int 1996 52 Yes YesNoAhmad et al Diabetes Care 1996 103 Yes YesNoNielsen et al Diabetes Care 1997 36 Yes YesNoUKPDS et al Br Med J 1998 758 Yes NoNoFogari et al J Hum Hypertens 1999 107 Yes NoNo ABCD Diabetes Care 2000 470 Yes YesNoRuggenenti et al (REIN) 352 (27)** Yes Yes Yes**Am J Kidney Dis 2000 MICRO-HOPE** Lancet 2000 3577 Yes NoYes***
GFR=glomerular filtration rate
*Reduction in the risk of end-stage renal disease (renal transplant or dialysis) **Only 27 (8%) of the 352 patients in this study were Type 2 diabetics***In this study there was no reduction of risk for renal dialysis for ramipril compared to placebo (p=0.70)
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Controlling the Course of Controlling the Course of Renal Disease with LosartanRenal Disease with Losartan
Rationale for RENAAL (Losartan Renal Protection Study):• Losartan significantly lowered BP comparable to other classes
of antihypertensive drugs• Losartan demonstrated superior tolerability compared to other
classes of antihypertensive drugs (placebo-like side-effect profile)• Losartan was a specific antagonist of angiotensin II (significant driver
of pathology in renal disease)• Losartan had significant renoprotective effects in animal models
of renal disease• Losartan was well tolerated and lowered BP in hypertensive patients
with renal insufficiencyBP=blood pressure
Adapted from Goa KL, Wagstaff AG Drugs 1996;51(5):820-845; Goldberg AI et al J Hypertens 1995;13(suppl 1):S77-S80;Lafayette RA et al J Clin Invest 1992;90:766-771; Remuzzi A et al J Am Soc Nephrol 1993;4(1):40-49; Toto R et al Hypertension 1998;31:684-691.
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Effect of Losartan on MicroalbuminuriaEffect of Losartan on MicroalbuminuriaU
rin
ary
alb
um
in (
mg
/24
hr)
Type 2 diabetesType 1 diabetesRenal transplantHypertension
0
50
100
150
200
250
30
22
n=12
37
15
n=9
57
40
n=10
83
39
n=194
92
60
n=103
115
66
n=424
153
55
n=14
188
94
n=8
211
173
n=40
21
15
n=29
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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
Adapted 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
Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334.
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• 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
Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334.
RENAAL RENAAL Secondary HypothesisSecondary Hypothesis
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RENAAL RENAAL Study DesignStudy Design
qd=once daily
*CTx=conventional therapy: Open-label calcium-channel blocker, diuretic, beta blocker, alpha blocker, or centrally acting agents.
Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334.
4 wk
Losartan 100 mg qd(+CTx)
Maintain conventional antihypertensive therapy (CTx)*
(excluding ACE inhibitors, AII antagonists)
Losartan 100 mg qd (+CTx)
Placebo(+CTx)
Goal trough BP:<140/<90 mmHg
n=1513
Placebo (+CTx)
Losartan 50 mg qd(+CTx)
Placebo(+CTx)
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
Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334.
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Europe19%
Latin America18%
North America 46%
Asia17%
Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334.
RENAAL RENAAL Enrollment by RegionEnrollment by Region
N=1513N=1513
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Losartan (+CTx) Placebo (+CTx)(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
Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334.
RENAAL RENAAL Baseline CharacteristicsBaseline Characteristics
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RENAAL RENAAL Primary Composite Endpoint and ComponentsPrimary Composite Endpoint and Components
Losartan (+CTx) Placebo (+CTx) 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
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.
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
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.
RENAAL Primary Components
Doubling of sCr
Months
% w
ith
ev
ent
RR: 25% p=0.006
Placebo (+CTx) 762 689 554 295 36 Losartan (+CTx) 751 692 583 329 52
RR: 20%p=0.010
Placebo (+CTx) 762 715 610 347 42 Losartan (+CTx) 751 714 625 375 69
0 12 24 36 48
0
10
20
30
40
50
0 12 24 36 480
10
20
30
Placebo (+CTx) 762 715 610 347 42 Losartan (+CTx) 751 714 625 375 69
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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 (+CTx) 762 689 554 295 36 760 584 431 214 24 Losartan (+CTx) 751 692 583 329 52 746 612 479 263 36
ITT analysis Per-protocol analysis
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869; Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.
0 12 24 36 480
10
20
30
40
50
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RENAALRENAALTime to ESRD from Doubling of sCrTime to ESRD from Doubling of sCr
Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.
Months
% w
ith
eve
nt
0 6 12 18 24
0
20
40
60
80
RR: 30%p=0.013
Placebo (+CTx) 198 111 48 11 4Losartan (+CTx) 162 104 43 19 3
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Baseline Year 1 Year 2 Study End
Systolic/diastolicLosartan (+CTx) 152/82 146/78 143/77 140/74Placebo (+CTx) 153/82 150/80 144/77 142/74
Mean arterial pressureLosartan (+CTx) 105.5 100.9 99.1 95.9Placebo (+CTx) 106.0 103.1 99.7 96.8
Pulse pressureLosartan (+CTx) 69.4 67.8 66.2 66.7Placebo (+CTx) 70.8 69.8 67.1 67.4
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869; Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.
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
Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.
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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.
Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.
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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
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.
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RENAAL RENAAL Secondary Composite EndpointSecondary Composite Endpoint
and Componentsand Components
Losartan (+CTx) Placebo (+CTx) 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
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.
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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 (+CTx) 762 685 616 375 53Losartan (+CTx)751 701 637 388 74
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.
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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.
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.
Placebo (+CTx) 762 632 529 390 130Losartan (+CTx)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 (+CTx) Placebo (+CTx)0
–0.02
–0.04
–0.06
–0.08
dl/m
g/y
r
–0.056
–0.069
p=0.0118% reduction
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.
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RENAALRENAALMost Common Clinical and Laboratory Adverse Most Common Clinical and Laboratory Adverse
Experiences Leading to Discontinuation of Study TherapyExperiences Leading to Discontinuation of Study Therapy
Heartfailure
ESRD MI Stroke Worseningrenal
insufficiency
sCr Hyper-kalemia
Per
cen
tag
e
Losartan (+CTx) Placebo (+CTx)
LaboratoryClinical
6
2
3
1
2
1 1 1 1
2
1 10.4
0
2
4
6
3
Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.
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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.
Adapted 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.
Adapted 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 first hospitalization for heart failure
– These benefits were largely independent of BP
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.
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RENAAL RENAAL Summary (Summary (IIII) )
• In patients with Type 2 diabetes and nephropathy– Losartan and placebo, added to CTx, 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
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.
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RENAALRENAALConclusionsConclusions
• Losartan conferred significant benefits on renal outcomes in Type 2 diabetic patients with nephropathy
• Losartan therapy resulted in a significant reduction in first hospitalizations for heart failure
• These benefits of losartan were independent of achieved BP control
• Losartan was generally well tolerated
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.
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• RENAAL results show that losartan + CTx– 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 suggested potential of losartan for substantial healthcare savings
RENAAL RENAAL Losartan Renal Protection StudyLosartan Renal Protection Study
Adapted 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
Adapted 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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Losartan Endpoint TrialsLosartan Endpoint Trials
ELITE II—The losartan heart failure survival study No significant difference was observed between treatment with losartan or captopril on all-cause mortality in HF patients, but losartan was significantly better tolerated
RENAAL—The losartan renal protection study Losartan provided renal protection and a cardioprotective benefit with excellent tolerability
LIFE—The losartan hypertension survival studyLosartan provided protection against stroke and new-onset diabetes
OPTIMAAL—The losartan post-MI survival studyLosartan provided cardiovascular benefits comparable to captopril
ELITE=Evaluation of Losartan in the Elderly; LIFE=Losartan Intervention For Endpoint reduction; OPTIMAAL=Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan
Adapted from Pitt B et al Lancet 2000;355:1582-1587; Brenner BM et al N Engl J Med 2001;345(12):861-869; Dahlöf B et al Lancet 2002;359:995-1003; Dickstein K et al Lancet 09/01/02; available at http://image.thelancet.com/extras/02art6111web.pdf.
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ReferencesReferences
Please refer to notes page.
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References References (cont’d)(cont’d)
Please refer to notes page.
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References References (cont’d)(cont’d)
Please refer to notes page.
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