acei inhibitors slideshare

Dilemmas in clinical decision making

ACEI inhibitors in

patients

with

Renal dysfunction

Dr. Shishu Shankar MishraProfessor. & 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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The Squibb group2/37

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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RAS & AT RECEPTORS Renin-angiotensin-aldosterone

system: and where inhibitors act. Opie2012

DR. S. S. MISHRA4/37

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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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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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

NormalIncreased

risk

Kidney

failureDamage GFR


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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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 FailureRenal 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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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

deathsReduce 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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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


Albuminuria as a Risk Factor for CVD in PREVEND

Hillege HL et al. Circulation 2002: 106: 1777-1782


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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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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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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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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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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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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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 seenin 2.5 – 31% in patients of CKD

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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. 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 nephropathythough proteniuria is reduced Hyperkalemia

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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

vasodilatoryprostaglandins

Increased

angiotensin II

Low GFR

Decreased

vasodilatory

postaglandins

Increased

angiotensin II

Low GFR

Slightly

increased

vasodilatory

postaglandins

Increased

angiotensin II

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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 MicroalbuminuriaReduction 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


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 vsplacebo.

Imai 2011 ORIENT (Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial)

2011 Olmesartan 10–40 mg/day vs placebo.

Haller 2011ROADMAP (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. 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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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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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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DR. S. S. MISHRA

To RAS or Not to RAS ?

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DR. S. S. MISHRA

Renal Protection vs. Damage

Protection

Damage

Issues

1. AKI

2. Creatinine3. Proteinuria

4. Hyperkalemia5. Renal flow

6. Hypotension

7. Drug Interaction

ACEI, ARBs, Diuretic + NSAID = Nephrotoxic combination = ARF

Cyclosporine, Lithium, Transplantation, Immuno suppressive drugsCiclosporin, 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

NephronScleroderma

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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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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.


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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:


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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


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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