ACE / ARB: renovascular hypertension and nephroprotection

Johan RosmanRenal Physician and CMOSpecialist in Hypertension

Waitemata DHB, andApollo Centre , Albany

info@bloodpressure.org.nz

Omapere, October 09

A fascinating animal for BP research

Why does a giraffe not faint ?

• Has a heart of 15 kilo’s• Has twice the human

blood pressure• Has a very interesting

autonomic nerve system• Has a large number of

pressure sensors in his carotid arteries

• Has a different R A A System, poorly understood

What maintains our normal BP ?Intravascular volumeAutonomic nervous systemRenin Angiotensin Aldosterone System

(RAAS)Vascular mechanisms

The 2 determinants of BP are Cardiac output Peripheral resistance

-BlockersACE InhibitorsAT1 Blockers

Direct renin inhibitors1-Blockers2-Agonists

All CCBsDiuretics

SympatholyticsVasodilators

-Blockers

Non-DHPCCBs

Diuretics

BloodPressure = Cardiac

Output

ACE = angiotensin-converting enzyme; AT1 = angiotensin type 1;CCBs = calcium channel blockers; DHP = dihydropyridine

Antihypertensive Drug Classes: Action Sites

Total PeripheralResistance

Ant

ihyp

erte

nsiv

e D

rug

Cla

sses

“Nobody goes there anymore; it’s too crowded”

Yogi Berra

Future antihypertensive treatment:

Importance of BP control

Hypertension - causes90 % ‘essential hypertension’10 % ‘secondary hypertension’ (probably

underestimatedOf these 10% probably 8% renal artery

stenosis (RAS)

Important to make the distinction !

Suggestive of sec hypertensionSevere or refractory hypertension. An acute rise in blood pressure over a

previously stable value. Proven age of onset before puberty. Age less than 30 years in non-obese, non-

black patients with a confirmed negative family history of hypertension

Case studyMrs G is a 54 year old lady with diabetes, moderately

controlled on oral antidiabeticsShe was always normotensive, but recently you find

bloodpressures of 190/105 with a normal pulse rateYou prescribe an ACE inhibitor, as she is also

proteinuric with 3.4 g/L of proteinuriaFor oedema she is treated with frusemide 40 mg ODThree weeks later you get a call that she is in hospital

with acute renal failureWhat happened ?

MRA Gadolinium-enhanced

Case studyMr. C, 79 years old, known with prostate

carcinomaSince 6 months worsening hypertension and

proteinuriaMRA and isotope nephrography requested

Case studyMr. C, 79 years old, known with

prostatecarcinomaSince 6 months worsening hypertension and

proteinuriaMRA and isotope nephrogram: virtually

occluded left renal artery

Would you give this man an ACE inhibitor ?

ACE Inhibition and RAS

IT STARTSHERE :

Who should be screened for RAS ? (1)Onset of hypertension before the age of 30 years,

particularly if there is a negative family history and no other risk factors for hypertension (eg, obesity).

Onset of severe hypertension ( ≥160/100 mmHg) after the age of 55 years.

Refractory or resistant hypertension, in a patient adhering to therapeutic doses of three appropriate antihypertensive agents (including a diuretic)

Acute rise in blood pressure over a previously stable baseline in patients with previously well-controlled hypertension (and includes patients with known renal artery stenosis who may have worsening stenosis)

Malignant hypertension (eg, patients with severe hypertension and signs of end-organ damage)

Who should be screened for RAS ? (2)Moderate to severe hypertension in a patient

with an unexplained atrophic kidney or asymmetry in renal sizes of >1.5 cm.

Moderate to severe hypertension in patients with diffuse atherosclerosis, particularly those over age 50.

Moderate to severe hypertension in patients with recurrent episodes of acute (flash) pulmonary edema or otherwise unexplained heart failure.

An acute elevation in the plasma creatinine concentration that occurs after the institution of therapy with an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB).

Advantages of blocking RAASPossible by blocking Angiotensin Converting

EnzymePossible by directly blocking the angiotensin

II receptor

Excellent blood pressure loweringCardioprotectiveReduction of strokeRenoprotectiveReducing renal protein lossReduces incidence of diabetes

Renal haemodymacical consequences of ACE and ARBDraw on board

Antihypertensive and Antiproteinuric Responses to an Increasing Dose of an Angiotensin-Converting Enzyme Inhibitor*

Palla R, et al. Int J Clin Pharmacol Res. 1994;14:35-43.

-80-70-60-50-40-30-20-10

0

% R

educ

tion

from

Con

trol

Blood PressureUrine Protein

5 mg 10 mg 15 mg 20 mg

Lisinopril Dose

Relative Risk Reduction With ACEIs in ABCD, CAPPP and FACET

-24

-43

-63

-51

-70

-60

-50

-40

-30

-20

-10

0

% r

elat

ive

risk

red

ucti

on

Pahor M, et al. Diabetes Care. 2000;23:888-892.

Acute Myocardi

al Infarction

Cardiovascular Event Stroke

All-cause Mortality

P<0.001

P<0.001

P=0.01

NS

Angiotensin II Receptor BlockersNo generalised effects, sits directly on the

receptorIt does not have a systemic effect

(bradykinin/kallikrein), still works as good as ACE

Effects and benefits comparable to ACE inhibitorsSimilar cardio- and renoprotectionLike ACE, reduces risks beyond just BP

reductionHowever significantly less side effects (as

only AH agent comparable to placebo !)ARB’s reduce risk of new onset diabetes

Antiproteinuric effects of AT 1 RB

What is better: block ACE or AR ?(here given in same patient)

The Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan Study

RENAAL OverviewRandomized multicentre, double-blind, placebo-

controlled study to evaluate the renal protective effects of the angiotensin II receptor antagonist losartan in patients with type 2 diabetes and nephropathy

Population1,513 patients (31 to 70 years old)

Diagnosed type 2 diabetes and nephropathy albumin/creatinine ratio 300 mg/g serum creatinine between 1.3–3.0 mg/dL (1.5–3.0

mg/dL for men >60 kg)

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

RENAAL Summary of Important Findings

In patients with type 2 diabetes and nephropathy:Losartan, in combination with other antihypertensive

therapy (non-ACE or ARB), delayed the onset of the primary composite endpoint* (P=0.02) and delayed progression to end stage renal disease (P=0.002)

Losartan reduced proteinuria (P<0.001) and the rate of decline in renal function (P=0.01)

Losartan reduced the incidence of first hospitalization for heart failure (P=0.005)

These benefits were above and beyond those attributable to blood pressure reduction alone

*Composite of a doubling of serum creatinine, end stage renal disease, or death

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

“If you don’t know where you are going, be careful. You may not get there”

Yogi Berra

Future antihypertensive treatment:

Reprinted from Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661 with permission from National Kidney Foundation.

National Kidney Foundation Algorithm for Achieving Target BP Goals in Hypertensive Diabetic Patients

Start ACE inhibitor titrate upwards

If BP still not at goal

(130/80 mm Hg)

BP still not at goal

(130/80 mm Hg)

Baseline pulse <84Add low-dose

beta blocker or alpha/beta blocker

Add other subgroup of CCB(ie, amlodipine-like agent if verapamil or diltiazem already being used and

the converse)

Refer to a clinical hypertension specialist

BP still not at goal (130/80 mm Hg)

If BP goal achieved, convert to fixed dose combinations (ACE inhibitor + CCB

or ACE inhibitor + diuretic)

Baseline pulse 84Add Thiazide Diuretic or

long-acting CCB*

Blood pressure >130/80 mm Hg

*If proteinuria present (>300 mg per day) non-DHP preferred.

Diabetes: Tight Glucose vs Tight BP Control and CV Outcomes in UKPDS

StrokeAny Diabetic

EndpointDM

DeathsMicrovascularComplications

-50

-40

-30

-20

-10

0

% R

educ

tion

In R

elat

ive

Ris

k

Tight Glucose Control (Goal <6.0 mmol/l or 108 mg/dL)

Tight BP Control (Average 144/82 mmHg)

32%

37%

10%

32%

12%

24%

5%

44%

*

*

**

*P <0.05 compared to tight glucose control

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.Reprinted by permission from WB Saunders.

“If you come to a fork in the road: take it !”

Yogi Berra

Is two better than one ??Modern EBM decision making:

The COOPERATE Trial260 patients with non-diabetic renal diseaseRandomly assigned to 100 mg losartan, or 3

mg trandolapril or combinationEndpoint: doubling of serum creatinine (loss

of renal function)Secondary point: proteinuria

The COOPERATE trial, con’t

Interesting recent articleStuart L. Linas: Are two better than one? ACE

Inhibitors plus ARB for reducing blood pressure and proteinuria in kidney disease. Clin J Am Soc Nephrol 3: S17-S23, 2008

Concluded:Many smaller combo trials now donePotential safety issues (hypothetical): hyper-K, loss of

renal function in advanced stagesStrong individual differences, race differences, dose

finding issuesStrongest effect on proteinuria, how this translates to

slowing the progression of renal function loss still unclear, despite COOPERATE (COOPERATE had many design flaws) and ONTARGET

No benefit on other outcomes (cardiovascular, stroke etc)

“Its tough making predictions, especially about the future”

Yogi Berra

Future antihypertensive treatment:

New drugs classesRenin inhibitors: AliskirenAVOID trial:

600 patients with proteinuriac diabetic nephropathy

Randomly assigned to Losartan monotherapy and Aliskiren plus Losartan

The combination treatment gave an additional 20% reduction in proteinuria

No additional serious side effects

The key to good careCommunicationCommunicationCommunication

021- KIDNEY(021-543639)info@bloodpressure.org.nz

Are there any questions to my answers ?

(Henry Kissinger, 1976)