To RAS or Not to RAS, in presents of CKD - For & Caution in use of ACEI in patients of chronic renal disease.

1. Dilemmas in clinical decision making
ACEI inhibitors
in
patients
with
Renal dysfunction
Dr. Shishu Shankar Mishra
Professor. & Director
Dept. of Cardiology
HI-TECH MEDICAL COLLEGE, BBSR
Sr. Consultant Cardiologist
MED ‘N’ HEART CLINIC, Cuttack.
Slide share - 9.8.2017
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2. The Squibb group
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3. ACEI
Bezazepril
Captopril
Enalapril
Lisinopril
Moexipril
Perindopril
Quinapril
Ramipril
Trandolapril
Cilazopril
Dela-pril
Fasinopril
Imidapril
Siprapril
Zofenopril
Quinapril
DR. S. S. MISHRA
RAAS Inhibitors
ARB
Candesartan
Eprosartan
Irbesartan
Losartan
Olmesartan
medoxomil
Telmisartan
Azilsartan
Valsartan
DRI -
Aliskiren
Pharmacokinetic patterns of prodrugs that are converted to active diacids and
then excreted (Class II). The predominant pattern for most is renal excretion
but with some drugs, especially fosinopril, biliary and fecal excretion may be
as important. (Figure © LH. Opie. 2012 and adapted from Angiotensin-
Converting Enzyme Inhibitors. The Advance Continues, 3rd ed, Authors'
Publishing House. New York & University of Cape Town Press. 1999.)
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4. RAS & AT RECEPTORS Renin-angiotensin-aldosterone
system: and where inhibitors act.
Opie2012
DR. S. S. MISHRA4/37

5. DR. S. S. MISHRA
1. Heart Failure, all stages
2. Hypertension especially in high-risk patients and in diabetics
3. AMI, acute phase for high-risk patients, post-infarct LV
dysfunction
4. Nephropathy, non-diabetic and diabetic type 1
5. Cardiovascular protection in specified doses (Ramipril,
Perindopril, Trandolapril)
6. Scleroderma crisis
ACE, Angiotensin-converting enzyme; AMI, acute myocardial infarction; LV, left ventricular.
Indications for ACE Inhibitors Based on Trial Data
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6. DR. S. S. MISHRA
1. ACEI - start and continue indefinitely with LV EF = 40% and in those with
HTN, DM or CKD, unless contraindicated. (Class I, Level of Evidence: A)
It is reasonable to use ACE inhibitors in all other patients. (Class IIa, Level: B )
1. ARBs for ACE intolerant pts with HF, post-MI with EF<40%. (Class I, level:A)
It is reasonable to use ARBs in other ACE-intolerant patients. (Class IIa, Level: B)
2. ARB + ACEI is not well established in systolic HF. (Class IIb, Level : A)
3. Aldosterone blockade in post MI patients without significant renal dysfunction or
hyperkalemia and already receiving and ACE inhibitor and b-blocker with LV EF <
40% plus either with diabetes or HF. (Class I, Level: A)
ACE inhibitors and Other RAAS inhibitors for Secondary
Prevention in CHD and Other Atherosclerotic Disease
(AHA/ACC foundation recommendation)
ACC , American College of Cardiology: ACE, angiotensin converting enzyme : AHA American Heart Association: ARB, angiotensin
receptor blocker: CHD, coronary heart disease; EF, ejection fraction; HF heart failure; LV, left ventricular; MI, Myocardial infarction.
From Smith Jr SC. Secondary prevention and risk reduction therapy for patients with coronary and other atherosclerosis vascular
disease: 2011 update: a guideline form the AHA and ACC Foundation. Circulation 2011:124:2458-2473
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7. CKD
death
Stages in Progression of Chronic Kidney
Disease and Therapeutic Strategies
Complications
Screening
for CKD
risk factors
CKD risk
reduction;
Screening for
CKD
Diagnosis
& treatment;
Treat
comorbid
conditions;
Slow
progression
Estimate
progression;
Treat
complications;
Prepare for
replacement
Replacement
by dialysis
& transplant
Normal
Increased
risk
Kidney
failure
Damage  GFR
DR. S. S. MISHRA7/37

8. AJKD 2002: 39(2)
 Kidney damage for > 3 months with or with out decreased
GFR, as manifest by either
Pathologic abnormalities; or Markers of kidney damage,
including abnormalities in blood, or
in urine , or
in imaging tests
 GFR <60 mL/min/1.73m2
for >3months with or without kidney damage
DR. S. S. MISHRA
Definition of Chronic Kidney Disease
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9. DR. S. S. MISHRA
eGFR
Stage I = < 90ml/min / 1.73m2
Stage II = 60-89ml/min / 1.73m2
Stage III = 30-59ml/min / 1.73m2
Stage IV = 15-29ml/min / 1.73m2
Creatinine clearance ml/min = 140 - Age × body weight
Cockcroft-Gault Equation Plasma creatinine × 72
Ex – 60 kg - 50yrs
Cr.1: 3mg = 140 – 50 × 60 / 3 × 72 = 25
Cr.2: 1mg = 140 – 50 × 60 / 1 × 72 = 75
Cr.3: 6mg = 140 – 50 × 60 / 6 × 72 = 12.5
Renal Failure
Renal Failure …. (1) Acute (2) Chronic (3) Acute on Chronic
(0.85 if female)
MDRD Equation2
GFR(ml/min/1.73m2)=
170 (Scr)-0.999(Age)-0.176(SUN)-0.170(Alb)+0.318
(0.762 if female)(1.180 if black)
eGFR
Plama Creatinine
Proteinuria
• N= <150mm/day
• Micro ALB - 30-300/Lt
• Nephro-protein = >3g/day
Normal GFR Male = 85-125, Female = 75-115
Plasma Normal value 0.5 - 1.5 mg/dl 8 times normal = 75% damage
Creatinine 2 times normal = 50% damage 10 times normal = 90% damage
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10. Summary of Evidence of the Effectiveness of the ACEIs
DR. S. S. MISHRA
Drug
(Genetric
Name)
People with Heart
Failure
People who
Have Had a
Heart Attack
People who have
Diabetes and Other Heart
Risk facts
People with Kidney Disease
Reduce
Deaths
Improve
Quality
of Life
Reduce
Deaths
Reduce Risk of
Heart Attack or
stroke
Reduce
deaths
Reduce Risk of
Heart Attack or
stroke
Prevent Decline in
Kidney Failure,
and/or Reduce
Deaths
Bezazepril + ++
Captopril ++ ++ ++ ++ ++
Enalapril ++ ++ + ++
Fosinopril ++
Lisinopril + ++ ++ ++
Moexipril
Perindopirl 0 ++ 0
Quinapril 0 ++
Ramipril ++ ++ ++ ++ ++ ++ ++
Tradolapril ++ ++ ++ ++
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11. ACE Inhibitors and CKD Progression
Meta-analysis
• 11 randomized controlled trials comparing ACEI vs.
other medications in treatment of hypertension in
1860 non-diabetic patients with
CKD (S Cr=2.3).
• Results:
– ACE inhibitors lowered BP and proteinuria.
– ACE inhibitors decreased the combined risk of
progression of CKD and
development of ESRD by 30%
independent of BP lowering effects.
Jafar T, Ann Intern Med 135:73-87, 2001
DR. S. S. MISHRA11/37

12. Albuminuria as a Risk Factor for CVD in PREVEND
Hillege HL et al. Circulation 2002: 106: 1777-1782
DR. S. S. MISHRA12/37

13. 13/37

14. For patients with left ventricular systolic dysfunction:
• ARBs can be used as an alternative to ACE inhibition in symptomatic
patients intolerant of ACE inhibitor to improve morbidity and mortality
(class or recommendation I, level of evidence B).
• ARBs and ACE inhibitors seem to have similar efficacy on mortality and
morbidity in chronic heart failure (class of recommendation IIa, level of evidence B.)
• In acute myocardial infarction with signs of heart failure or left ventricular
dysfunction, ARBs and ACE inhibitors have similar or equivalent
effects on mortality (class or recommendation I, level evidence A)
• ARBs can be considered in combination with ACE inhibitors in patients
who remain symptomatic, to reduce mortality (class of recommendation IIa,
level of evidence B) and hospital admissions for heart failure (class
recommendation I, level of evidence A).
DR. S. S. MISHRA
The European Society of Cardiology guidelines comment
on Angiotensin II receptor blocker (ARB) usage
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15. DR. S. S. MISHRA
CONCLUSIONS —
Dual blockade of the
RAS provides superior
short-term
renoprotection
independent of systemic
blood pressure changes in
comparison with
maximally recommended
doses of ACEI in patients
with type 2 diabetes as
well as nephropathy.
ACEI + ARB
Short term renoprotection
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16. DR. S. S. MISHRA
Renoprotective effects of ACE inhibitors and ARBs
(large [n ~ or > 100] randomized controlled studies)
Dual renin-angiotensin system inhibition for prevention of renal and cardiovascular events:
do the latest trials challenge existing evidence? Mallat Cardiovascular Diabetology 2013, 12:108
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17. DR. S. S. MISHRA
Mechanisms of autoregulation of filtration. Maintenance of glomerular filtration pressure during reduced renal perfusion
pressure requires both angiotensin-II-dependent efferent vasoconstriction, and concomitant afferent vasodilation, by a
prostaglandin-dependent mechanism. RAAS-blockade blunts the efferent vasoconstriction, and NSAIDs block the afferent
component. This explains why GFR can decrease sharply when renal perfusion is decreased in patients on RAAS
blockade, by lack of efferent vasoconstriction, and why this is even worse during use of NSAIDs.
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18. DR. S. S. MISHRA
ACE inhibitors mechanism of action
and potential adverse effects
ACE inhibitors
Suppress
ACE
synthesis
Suppressed
Convertion of
Ang-I to Ang-II
Suppressed
aldosterone
production
Supress
bradykinin
breakdown
Inflammatory
pain
Dry cough
Angioedema
Acute renal
failure
Hyperkalemia
Hypotension
Volume
depletion
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19. Side Effects
DR. S. S. MISHRA
Adverse effects
of ACE Inhibitors
• Hypotension
• Renal insufficiency
• Cough
• Hyperkalemia
• Hyperreninemia
• Ageusia
• Skin rash
• Proteinuria
• Neutropenia
Captopril – Adverse effects
• Cough – persistent brassy cough in 20% cases – inhibition of
bradykinin and substanceP breakdown in lungs
• Hyperkalemia in renal failure patients with K+ sparing diuretics,
NSAID and beta blockers (routine check of K+ level)
• Hypotension – sharp fall may occur – 1st dose
• Acute renal failure: CHF and bilateral renal artery stenosis
• Angioedema: swelling of lips, mouth, nose etc.
• Rashes, urticaria etc
• Dysgeusia: loss or alteration of taste
• Foetopathic: hypoplasia of organs, growth retardation etc
• Neutripenia
• Contraindications: Pregnancy, bilateral renal artery stenosis,
hypersensitivity and hyperkalaemia
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20. DR. S. S. MISHRA
Percentage of patients with reported adverse effects of ACE inhibitors in clinical trials in patients
with CKD, with a follow-up of 1 year or more. Only trials with at least 50 patients are included.
(2.5%)
(31.5%)
ACEI - Adverse reaction is seen
in 2.5 – 31% in patients of CKD
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21. ACEI play a complex role in renal function in HF
• May improve CO in some patient and hence increase effective
renal perfusion
• ACEI may lower BP to the point where effective renal
perfusion is impaired
• With chronic renal disease, there is hyper-filtration in the
remaining nephrons. ACEI decreases efferent arteriole
constriction and hence decreases glomerular capillary
pressure which may preserve renal function long term
• This may result in a 10-20% increase in creatinine, but over
the long term renal function is preserved
DR. S. S. MISHRA21/37

22. DR. S. S. MISHRA
ARB & ACEI Trials in Diabetic Nephropathy
Acronym Reference Major Benefit
Collaborative
Study Group
N EngI J Med
1993;329:1456-1462.110
(ACEI)
Captopril protects against deterioration in renal function in
insulin-dependent diabetic nephropathy and is more effective
than BP control alone.
REIN Lancet 1997;349:1857-
1863.
(ACEI)
Ramipril safely reduces proteniuria and the rate of GFR
decline in chronic nephropathies with proteinuria of 3 g or
more per 24 hr.
ABCD N EngI J Med
1998;338:645-652.
(ACEI)
Enalapril for diabetes with hypertension gave a lower
incidence of MI than nisoldipine over 5 years of follow-up ,
a secondary end point needing confirmation.
AASK JAMA 2001;285:2719-
2728.88
(ACEI)
Ramipril, compared with amlodipine in African Americans
with hypertensive renal disease, retards progression of renal
disease and proteinuria.
RENAL N Eng J Med
2001;345:861-869. (ARB)
Losartan 50-100 daily. Reduced end-stage renal disease.
Mortality unchanged.
IDNT N Eng J Med
2001;345:870-878 (ARB)
Irbesartan 300mg daily reduced onset of diabetic
nephropathy.
ROADMAP N Engl J Med 2011;364:90
7-917 (ARB)
Olmesartan 40mg daily delayed onset of microalbuminuria.
Subgroup with preexisting coronary heart disease, higher CV
deaths.
VA-NEPHRON-D
(2013)
Clin J Am Soc Nephrol
2009;4:361-368 (ARB)
(Adverse effects in patients with diabetic nephropathy
though proteniuria is reduced Hyperkalemia
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23. Arteriolar resistances
DR. S. S. MISHRA
A. Normal perfusion pressure B. Normal perfusion pressure
C. Decreased perfusion pressure in the
presence of NSIDs
D. Decreased perfusion pressure in the
presence of ACEI or ARB
Normal GFR
Afferent
arteriole
Efferent
arteriole
Glomerulus
Tubule
Normal GFR
maintained
Increased
vasodilatory
prostaglandins
Increased
angiotensin II
Low GFR
Decreased
vasodilatory
postaglandins
Increased
angiotensin II
Low GFR
Slightly
increased
vasodilatory
postaglandins
Increased
angiotensin II
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24. Study Year Treatment regimen
IMPROVE 2007 Ramipril 10 mg/day + irbesartan 150–300 mg/day or
ramipril 10 mg/day + placebo; BP goal < 130/80
SMART (Shiga
Microalbuminuria
Reduction Trial )
2007 ARB / CCB
Kunz R 2008 2008 Dual therapy with ACEI + ARB vs ARB alone.
Kunz R 2008 Dual therapy with ACEI + ARB vs ACEI alone.
ONTARGET 2008 Ramipril 10 mg/day, telmisartan 80 mg/day, or both
ramipril + telmisartan; no BP goal.
Krairittichai,
Chaisuvannarat
2009 Enalapril 40 mg/day + telmisartan 80 mg/day or
enalapril 40 mg/day; BP goal < 130/80 mm Hg.
AVOID 2008,
2010
Losartan 100 mg/day + other antihypertensive drugs
to reach BP goal < 130/80 then randomized to
aliskiren 150–300 mg/day or placebo
Summary of Meta-Analyses, Reviews, and Recent Studies Evaluating
Dual versus Single Renin Angiotensin System Agents in Patients
with Diabetes, Chronic Kidney Disease, or Diabetic Kidney Disease
DR. S. S. MISHRA24/37

25. Study Year Treatment regimen
Mauer 2009 Enalapril 10–20 mg/day vs losartan 50–100
mg/day vs placebo
Bilous 2009 Candesartan 16 mg increased to 32 mg vs
placebo.
Imai 2011 ORIENT
(Olmesartan Reducing Incidence of End
Stage Renal Disease in Diabetic
Nephropathy Trial)
2011 Olmesartan 10–40 mg/day vs placebo.
Haller 2011
ROADMAP (Randomized
Olmesartan And Diabetes
MicroAlbuminuria Prevention)
2011 Olmesartan 40 mg/day vs placebo
Hirst 2012 ACEI or ARB vs placebo in 84% of the trials in
the meta-analysis.
Vejakama 2012 ACEI or ARB vs placebo.
Summary of Meta-Analyses, Reviews, and Recent Studies Evaluating Single
ACEI, ARBs, or Renin Inhibitors Versus Placebo in Patients with Diabetes,
Chronic Kidney Disease, or Diabetic Kidney Disease
DR. S. S. MISHRA25/37

26. DR. S. S. MISHRA
• MAP insufficient for adequate renal perfusion
• Poor cardiac output
• Low systemic vascular resistance
• Volume depletion (diuretic use)
• Presence of renal vascular disease
• Bilateral renal artery stenosis
• Stenosis of dominant or single kidney
• Afferent arteriolar narrowing (hypertension, cyclosporine A)
• Diffuse atherosclerosis in smaller renal vessels
• Vasoconstrictor agents (NSAIDs, cyclosporine)
Causes of ARF on Initiation of
ACE Inhibitor Therapy
Circulation is available at http://www.circulationaha.org
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27. DR. S. S. MISHRA27/37

28. DR. S. S. MISHRA
Year Study
2008 ONTARGET study Proteinuria but
dialysis
doubling serum creatinine
Hypotension
Syncope
No mortality benefit
2010 COOPERATE data 200,000USA patient on Dual therapy ACEI+ARB
2010 COOPERATE data Retracted the data validity
2010 Several studies Adverse effect of dual therapy
2012 DDOQI Guideline for HTN + CKD
Dual therapy side effect
2013 VA-Nephron-D Dual therapy
No benefit on eGFR
No benefit CVS event
Rates of AKI
Hyperkalemia ((76mg/Lt) requiring hospitalisation dialysis
Because of Hyperkalemia Hypotension AKI during ACEI therapy /
may occurs any time
One agent in optimal dose should be used
Some- Still believe that Dual therapy can give better results
RAAS trials at glance
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29. DR. S. S. MISHRA
Year Study
1977 ACEI MA Ondebtti, B, Rubin and DW Cushman
1990 ACEI Slaved progression of Renal Failure
Decreased proteinuria independent of HTN
It was postulated that proteinuria is
synonymous with nephro protein
Dual ACEI + ARB therapy
2003 COOPERATE Dual therapy better than mono-therapy
Slower CKD progression
2004 KDOQI Treat proteinuria to target < 500-1000mg/day
ACEI,ARBs or Dual therapy
RAAS trials at glance
200,000USA patient on Dual therapy ACEI + ARB
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30. DR. S. S. MISHRA30/37

31. DR. S. S. MISHRA
To RAS or Not to RAS ?
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32. DR. S. S. MISHRA
Renal Protection vs. Damage
Protection
Damage
Issues
1. AKI
2. Creatinine
3. Proteinuria
4. Hyperkalemia
5. Renal flow
6. Hypotension
7. Drug Interaction
ACEI, ARBs, Diuretic + NSAID = Nephrotoxic combination = ARF
Cyclosporine, Lithium, Transplantation, Immuno suppressive drugs
Ciclosporin, tacrolimus, mitomycin C, conjugated estrogens, quinine, 5-fluorouracil, ticlopidine, clopidogrel, interferon, valaciclovir, gemcitabine, bleomycin
RAAS Inhibitor
ACEI
ARB
ACEI + ARB
ACEI + ARB + DRI
CCF
HTN
CAD
Nephron
Scleroderma
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33. DR. S. S. MISHRA
1.BP goal <130/80 mm Hg - DKD and micro or macro-albuminuria.
<140/90mm Hg - normo-albuminuria- elderly pts, CVS disease;
therefore, individualize the BP goal.
2. ACEIs or ARBs as single-agent primary therapy in DKD, particularly
those with concurrent hypertension and micro- or macro-albuminuria.
3.Avoid Dual RAS therapy except under the care or recommendation of a
specialist (endocrinologist, nephrologist, diabetologist or cardiologist).
4.No RAS therapy with potassium >5.5 mEq/L
or diagnosed or suspected bilateral renal artery stenosis.
Maximising Efficacy & Minimizing harmful effect of
RAAS Inhibition in Nephropathy
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34. DR. S. S. MISHRA
5. Test serum creatinine and serum potassium concentrations before
ACEI or ARB initiation and with each dose increase.
6. Start with low doses of ACEIs or ARBs; Slowly up titrate
consider halving the lowest dose in patients at high risk for RAS agent –
induced AKI (elderly patients, patients with arthrosclerosis or patients diuretics
or are dehydrated).
7. Maximize ACEI or ARB - up titrate 2 to 4 weeks until the maximum
dose is achieved or hypotension or other adverse effects occur (see potassium
and serum creatinine concentration monitoring).
8. Check potassium and creatinine 2 weekly of initiating RAS agent or
dose increase.
Maximising Efficacy & Minimizing harmful effect of
RAAS Inhibition in Nephropathy
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35. DR. S. S. MISHRA
9. Dose tolerated with 30% or less increase from the baseline serum
creatinine or 30% or less increase in baseline eGFR,
consider dose increase.
10. If the serum creatinine increases more than 30% from baseline
or GFR is reduced more than 30% from baseline anytime within 4 months
of RAS initiation,
decrease the dose
(or stop the RAS agent if at lowest dose).
{Cut off level 2.5 to 3.0mg/dl}
Recommendations regarding changes in serum creatinine concentrations:
Maximising Efficacy & Minimizing harmful effect of
RAAS Inhibition in Nephropathy
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36. DR. S. S. MISHRA
11. If the potassium level is at or increases to 5.0 mEq/L, prescribe a low-
potassium diet.
12. If the potassium level increases to 5.5 mEq/L, measures such as adjustment
in diuretics, administration of long-term alkali supplements, liberalizing salt
intake, or long-term use of low dose sodium polystyrene sulfonate may be
indicated.
13. If the potassium level increases to 6.0 to less than 6.5 mEq/L, stop the RAS
agent and reinstitute at 50% of the prior dose when potassium is less than
5.5 mEq/L.
14. If potassium increases to 6.5 mEq/L or more, permanently discontinue the
RAS agent.
Recommendation regarding serum potassium levels
Maximising Efficacy & Minimizing harmful effect of
RAAS Inhibition in Nephropathy
Frequency of hyperkalaemia defined as serum potassium concentration >5.1 mmol/l (n%) in chronic kidney disease (CKD) patients treated or not treated
renin-angiotensin-aldosterone system (RAAS) blockade (angiotensin converting enzyme inhibitor (ACEI) or/and angiotensin II receptor blocker (ARB)).
1996 2001 2006 2011
No RAAS blockade n (%) 3 (2.1) 21 (8.4) 48 (7.2) 60 (13.6)
RAAS blockade
(monotherapy)
n (%) 4 (8.3) 15 (6.4) 128 (12.8) 140 (12.9)
Dual RAAS blockade n (%) - 1 (20.0) 20 (14.5)a 28 (16.7)
ap<0.01, no RAAS vs dual RAAS (2006).
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37. Thank you for sharing your time…..
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