Resistant Hypertension

Use of Anti hypertensive ARB/ACEI Issues

What is Resistant Hypertension

Blood pressure remaining above goal in spite of

concurrent use of 3 antihypertensive agents of
different classes.

Ideally, 1 of the 3 agents should be a diuretic &

all agents should be prescribed at optimal dose
amounts.

2008, American Heart Association. All rights reserved.

Definition Highlights
In Compliant
Patient
On life style
change

BP not on target
Three drugs used
One is a diuretic
At optimal dosage

Definition Highlights

Use of diuretic recommended but not required

before diagnosing resistant hypertension.

Doses should be optimal but not necessarily

maximal before diagnosing resistant hypertension.
Controlled resistant hypertension: high blood
pressure controlled but with use of 4 of more agents
should be considered resistant.

2008, American Heart Association. All rights reserved.

Resistant HT: Introduction

(Contd)

This definition does not apply to patients who

have been recently diagnosed with HT
Moreover, resistant HT is not synonymous with
uncontrolled HT
Uncontrolled HT includes all hypertensive
patients who lack BP control under treatment,
namely,
those receiving an inadequate treatment regimen,
those with poor adherence, and those with
undetected secondary HT, as well as those with
true treatment resistance J Am Coll Cardiol 2008;52:174957

Resistant HT: Introduction

(Contd)

Patients with resistant HT may

achieve BP control with full doses
of
4 or more antihypertensive
medications

J Am Coll Cardiol 2008;52:174957

Prevalence

Prevalence is unknown, but observational and clinical trials

suggest it is a common clinical problem.

In a recent analysis of National Health and Nutrition

Examination Survey (NHANES) participants being treated for
hypertension, only 53% were controlled to <140/90 mm Hg. 1
Of NHANES participants with CKD, only 37% were
controlled to <130/80 mm Hg2 and only 25% of diabetic
participants were controlled to <130/85 mm Hg.1

In the Antihypertensive and Lipid-Lowering Treatment to

Prevent Heart Attack Trial (ALLHAT) after approximately 5
years of follow-up, 27% of participants were on 3 or more
medications.3

Hajjar I, Kotchen TA. JAMA 2003; 2Peralta CA et al. Hypertension 2005; 3Cushman WC et al. Clin Hypertens.

2008, American Heart Association. All rights reserved.

Resistant HT: Primary Cause

Office
resistance
6%
Psychological
causes
9%
Secondary
HTN
5%

Interfering
substances
1%

Unknown
6%

Nonadherence
16%

Cause of resistance
found in 133/141
94% (83/91 91%)
cases

Drug-related
causes
58%

Am J Hypertens 2003;16:925-930

Pseudo-resistance
Lack of BP control with appropriate
treatment in a patient who does not
have resistant hypertension
Factors include
Suboptimal BP measurement
technique;
The white-coat effect; and
Poor adherence to prescribed therapy
J Am Coll Cardiol 2008;52:174957

Pseudo-resistance

(Contd)

Causes of Pseudo-Resistant Hypertension

J Am Coll Cardiol 2008;52:174957

Factors Contributing to Resistant HT

J Am Coll Cardiol 2008;52:174957

Causes of Resistance to
Hypertension Treatment

Poor adherence with prescribed medications

Inaccurate blood pressure measurement

White coat hypertension

2008, American Heart Association. All rights reserved.

Substances that Can Interfere with Blood

Pressure Control

Non-Narcotic Analgesics
- Non-steroidal anti-inflammatory agents including aspirin
- Selective COX-2 inhibitors

Sympathomimetic agents
- decongestants
- diet pills
- cocaine

Stimulants
-methylphenidate
-dexmethylphenidate,
-dextroamphetamine
- amphetamine, methamphetamine
-modafinil

2008, American Heart Association. All rights reserved.

Substances that Can Interfere with Blood

Pressure Control

Alcohol

Oral contraceptives

Cyclosporine

Erythropoietin

Natural licorice

Herbal compounds

2008, American Heart Association. All rights reserved.

-ephedra
- ma huang

Secondary Causes of Resistant Hypertension

Common
Obstructive sleep apnea
Renal parenchymal disease
Primary aldosteronism
Renal artery stenosis

2008, American Heart Association. All rights reserved.

Secondary Causes of Resistant Hypertension

Uncommon

Pheochromocytoma

Cushings disease

Hyperparathyroidism

Aortic coarctation

Intracranial tumor

2008, American Heart Association. All rights reserved.

Evaluation of Resistant Hypertension

Confirm appropriate treatment

Identify causes
- Secondary?
Document target organ damage

2008, American Heart Association. All rights reserved.

Resistant Hypertension: Diagnostic and

Treatment Recommendations
Confirm Treatment Resistance
Office blood pressure >140/90 or 130/80 mm Hg in patients
with diabetes or chronic kidney disease
and
Patient prescribed 3 or more antihypertensive medications
at optimal doses, including if possible a diuretic
or
Office blood pressure at goal but patient requiring 4 or
more antihypertensive medications
2008, American Heart Association. All rights reserved.

Exclude Pseudoresistance
Is patient adherent with prescribed regimen?
Obtain home, work, or ambulatory blood pressure
readings to exclude white coat effect

Identify and Reverse Contributing Lifestyle Factors

Obesity
Physical inactivity
Excessive alcohol ingestion
High salt, low-fiber diet
2008, American Heart Association. All rights reserved.

Discontinue or Minimize Interfering Substances

Non-steroidal anti-inflammatory
agents
Sympathomimetics
- Diet pills
- Decongestants
Stimulants
Oral contraceptives
Licorice
Ephedra
2008, American Heart Association. All rights reserved.

Screen for Secondary Causes of Hypertension

Obstructive sleep apnea (snoring, witnessed apnea, excessive daytime

sleepiness)
Primary aldosteronism (elevated aldosterone/renin ratio)
Chronic kidney disease (creatinine clearance <30 mL/min)
Renal artery stenosis (young female, known atherosclerotic disease,
worsening renal function)
Pheochromocytoma (episodic hypertension, palpitations, diaphoresis,
headache)
Cushings disease (moon facies, central obesity, abdominal striae,
inter-scapular fat deposition)
Aortic coarctation (differential in brachial or femoral pulses, systolic
bruit)
2008, American Heart Association. All rights reserved.

Treatment of Resistant Hypertension

Non-Pharmacologic Recommendations
Weight loss
Regular exercise (at least 30 min most days of the week)
Low dietary salt ingestion (<100 mEq sodium/24-hr)
Moderate alcohol ingestion (no more than 2 drinks per
day for most men and 1 drink per day for women or
lighter weight persons)
Ingestion of low-fat, high-fiber diet
Treat obstructive sleep apnea if present
2008, American Heart Association. All rights reserved.

Treatment of Resistant Hypertension

Pharmacologic Recommendations
Withdrawal or down titration of interfering substances as possible

Use of a long-acting thiazide diuretic, preferably chlorthalidone

Combine agents with different mechanisms of action

Recommended triple regimen of

-ARB or ACE inhibitor
- Calcium channel blocker
-Thiazide diuretic

2008, American Heart Association. All rights reserved.

Treatment of Resistant Hypertension

Consider addition of mineralocorticoid receptor antagonist

Use of loop diuretic may be necessary in patients with CKD

(creatinine clearance <30 mL/min)

2008, American Heart Association. All rights reserved.

J Am Coll Cardiol 2008;52:174957

Journal of Human Hypertension 2004;18:139185

What additional agents to add?

What combinations work?

Diuretics
Studies indicate that patients with
resistant HT
Frequently have inappropriate
volume expansion contributing to
their treatment resistance such that
a diuretic is essential to maximize
BP control
In most patients, use of a longacting thiazide diuretic will be most
effective
Circulation. 2008;117:e510-e526

Diuretics

(Contd)

In a blinded comparison of
hydrochlorothiazide 50 mg and
chlorthalidone 25 mg daily, the latter
provided greater 24-hour ambulatory blood
pressure reduction, with the largest
difference occurring overnight
Given the outcome benefit demonstrated with
chlorthalidone and its superior efficacy
compared with hydrochlorothiazide,
Chlorthalidone should be preferentially used in
patients with resistant HT
Circulation. 2008;117:e510-e526

Diuretics

(Contd)

In patients with oedema or more

advance renal impairment, for
example, serum creatinine >200
mmol/l,
Thiazide/thiazide-like diuretics may be
ineffective and a
Loop diuretic (eg furosemide) may be
required, often in higher doses than
Journal of Human Hypertension 2004;18:139185
used conventionally

Mineralocorticoid Receptor Antagonists

Consistent with reports of a high
prevalence of primary
aldosteronism in patients with
resistant HT have been studies
demonstrating that
Mineralocorticoid receptor
antagonists provide significant
antihypertensive benefit
when
Circulation.
2008;117:e510-e526

Mineralocorticoid Receptor Antagonists

(Contd)

Spironolactone
Used for resistant HT with normal
aldosterone levels, 12.5-50mg/daily
Additional benefits: antiproteinuric,
improves heart failure survival
(RALES)
10% gynecomastia

Drug Combinations
Chlorthalidone 25mg + spironolactone 12.5-50 mg

Excellent diuretic maximization, also vs hypokalemia

Chlorthalidone, can

s. K+ enough to cause cardiac arrest

Aldosterone blockers spironolactone eplerenone can

Protect vulnerable patients and

Significantly reduce BP resistant to 3 drugs,

A logical way to provide maximal anti-HT

efficacy and to prevent hypokalemia
might be a

Combination of chlorthalidone and

spironolactone 12.5/25.0 mg/d
Hypertension 2009;54;951-953

Drug Combinations

(Contd)

ACEI plus ARB

Mostly 4-8 week studies

Risk of ARF in animal studies
Additional reduction mild: 4/3 mm Hg
Best application in proteinuric patients

Direct Vasodilators
Hydralazine sequence is 25 BID to
50 BID to 100mg BID
Minoxidil sequence is 2.5mg, to
5mg, to 5mg BID, to 10 mg BID, to 20
mg BID
Need a BB and a diuretic on board
Watch for headache and fluid

Direct Vasodilators

Minoxidil

(Contd)

Excellent drug for resistant HT

Direct vasodilator causing reflex tachycardia and
fluid retention
Need BB on board to prevent myocardial ischemia
Dosage range 2.5mg to 20 mg BID
Temporarily discontinue drug with marked edema,
than restart with more diuretic
90% ST-T change within 2 weeks, later resolve

1-Adrenergic Receptor
Blockers
Not to be used for monotherapy:
ALLHAT (class effect)
May be used as an add-on for
resistant hypertension
May cause urinary incontinence,
especially in females, due to bladder
outlet relaxation

Additional Agents/ Devices

Combined alpha- and beta-blockers (labetalol,
carvedilol)
Reserpine 0.05-0.1 mg
Isosorbide vs augmentation pressure
Device-guided slow breathing exercises (Resperate)
Device-mediated electrical carotid sinus baroreceptor
stimulation
Thoracic bioimpedance measurements

Resistant HT: Newer

approaches
Under evaluation
Endothelial receptor antagonist
Catheter-based renal sympathetic
denervation

Endothelial receptor
antagonist
Class of agents that may prove useful for
resistant HT is endothelin-receptor antagonists
(ERAs)
In patients with mild-to-moderate essential HT,
both nonselective and selective (type A
receptor) ERAs
Produce BP reductions comparable to those of
common antihypertensive agents, but
Concerns about adverse events precluded their
use as a treatment option for uncomplicated
hypertension

Darusentan
However, a selective ERA recently tested in 115
patients with resistant HT,
Demonstrated a dose-dependent decrease in BP

The largest reductions (11.5/6.3 mm Hg) were

observed after 10 weeks of follow-up with the
largest dose, and
The drug was generally well tolerated
Ongoing phase III clinical trials with such
agents are awaited to provide further
information in this interesting field

Clin Hypertens (Greenwich) 2007;9:760 9

Darusentan

(Contd)

Lancet 2009
Randomised, double-blind study was
undertaken in 117 sites in North and
South America, Europe, New Zealand,
and Australia

Lancet 2009; 374:1423-1431

Darusentan

(Contd)

Results
The mean reductions in clinic
systolic and diastolic blood
pressures were

9/5 mm Hg (SD 14/8) with placebo,

17/10 mm Hg (15/9) with darusentan 50
mg,
18/10 mm Hg (16/9) with darusentan 100
mg,
18/11 mm Hg (18/10) with darusentan
300 mg (p<00001 forLancet
all effects)
2009; 374:1423-1431

Darusentan
Results

(Contd)

(Contd)

The main adverse effects were related to fluid

accumulation
Oedema or fluid retention occurred in 67 (27%)
patients given darusentan compared with 19 (14%)
given placebo
One patient in the placebo group died (sudden
cardiac death), and five patients in the three
darusentan dose groups combined had cardiacrelated serious adverse events
Lancet 2009; 374:1423-1431

Darusentan

(Contd)

Interpretation
Darusentan provides additional
reduction in blood pressure in
patients who have not attained their
treatment goals with three or more
antihypertensive drugs. As with other
vasodilatory drugs, fluid management
with effective diuretic therapy might
be needed
Lancet 2009; 374:1423-1431

Catheter-based renal
sympathetic denervation
Catheter-based renal sympathetic
denervation for resistant
hypertension: a multicentre safety
and proof-of-principle cohort study.
Lancet. 2009;373(9671):1275-1281.

Catheter-based renal
sympathetic denervation

(Contd)

Proof-of-principle study showing

that a
Novel catheter-based device produced
renal denervation and a substantial
decrease in blood pressure in a select
group of 45 patients with resistant HT

Lancet. 2009;373(9671):1275-1281

Catheter-based renal
sympathetic denervation

(Contd)

Systolic and diastolic BP after the

procedure (while maintaining
patients on their usual
antihypertensive medication
therapy) were decreased by
14/10, 21/10, 22/11, 24/11, and 27/17
mm Hg at 1, 3, 6, 9, and 12 months,
respectively

Lancet. 2009;373(9671):1275-1281

Catheter-based renal
sympathetic denervation

(Contd)

The development of this novel catheterbased technology offers

An opportunity for clinical investigators to
examine the impact of selective renal
denervation on resistant HT

For clinicians learning of this new

technology,
Data are too preliminary to rush to judgment
American Journal of Kidney Diseases,54;2009: pp 795-797

Catheter-based renal
sympathetic denervation

(Contd)

Hence, further rigorous

investigation is required to
Identify hypertensive patients who
might benefit from catheter-induced
renal sympathetic denervation

American Journal of Kidney Diseases,54;2009: pp 795-797

Comparing Two Kinds

of Anti Hypertensives
ACEIs and ARBs

Facts
ACEIs and ARBs are two of the many kinds of Anti Hypertensives
Both kinds of drugs (ACEIs and ARBs) do a good job of lowering blood
pressure.
ACEIs and ARBs rarely cause serious problems. The main difference in
side effects is that ACEIs are more likely than ARBs to cause a dry cough.
ACEIs and ARBs do not affect cholesterol levels or blood sugar levels.
Some ACEIs are available as generics, which cost less.

How do side effects of ACEIs and ARBs compare?

Both ACEIs and ARBs can cause cough, dizziness, and headache. The
chance of dizziness or headache is about the same with ACEIs and ARBs.
The main difference is that ACEIs are more likely to cause a dry cough.
Sometimes this cough is bad enough that people need to switch drugs. In
research studies:
8 out of 100 people taking an ACEI stop taking it because of side effects.
3 out of 100 people taking an ARB stop because of side effects.

Tell your doctor or nurse if you are bothered by one of these side effects.
But do not stop taking your medicine on your own.

Study of ARB(Losartan) & Lisinopril on Cough

BP lowering efficacy better than Captopril

Reductions in DBP mm of Hg

Reductions in SBP mm of Hg

British Hypertension Society state that

ACE inhibitor intolerance,
Diabetic nephropathy
Hypertension with left ventricular hypertrophy,
Heart failure in ACE inhibitor-intolerant patients post-MI
are all 'compelling indications' for the use of ARBs

ARBs as antihypertensive agents

Angiotensin receptor blockers are a popular first-choice
medicine for high blood pressure.
ARBs particularly recommended for people who are under
55 years.
Angiotensin receptor blockers can be useful for people
who have diabetes or kidney disease as well as high
blood pressure. This is because there is some evidence to
show that they can protect kidneys.

ARB (AT1 Blockers)

Losartan
Valsartan
Irbesartan
Candesartan
Telmisartan
Eprosartan
Olmesartan

Development of ARBs

1986 Losartan

Became the first

successful Ang II
antagonist drug

Valsartan,
1990
Candesartan
Irbesartan

Valsartan
nonheterocyclic ARB
Candesartan Prodrug
have stronger blood
pressure lowering
effects than and
losartan.
Irebesartan - longer
acting than valsartan &
losartan

1991Telmisartan

Telmisartan - longest
elimination half-life of
the ARBs or about 24
hours

1995Olmesartan

Olmesartan Newest
& Best ARB on the
market, marketed in
2002

ARB according to Guideline

Goal
Guideline Population BP(mm Hg)

JNC 8

Initial Drug Treatment Options

60 y

<150/90

Non-Black: thiazide, ACEI, ARB, or

CCB
Black: thiazide or CCB

<60 y

<140/90

Non-Black: thiazide, ACEI, ARB, or

CCB
Black: thiazide or CCB

Diabetes

<140/90

Thiazide, ACEI, ARB, or CCB

CKD

<140/90

ACEI or ARB

Guideline

Population

Goal BP(mm Initial Drug Treatment

Hg)
Options

ESH/
ESC
2013

General
nonelderly

<140/90

-Blocker, diuretic, CCB,

ACEI, or ARB

General elderly
<80 y

<150/90

-Blocker, diuretic, CCB,

ACEI, or ARB

General 80 y

<150/90

-Blocker, diuretic, CCB,

ACEI, or ARB

Diabetes

<140/85

ACEI or ARB

CKD no
proteinuria

<140/90

ACEI or ARB

CKD +
proteinuria

<130/90

Guideline

Population

Goal BP(mm
Hg)

Initial Drug
Treatment
Options

NICE
2011

General <80 y

<140/90

<55 y: ACEI or
ARB

General 80 y

<150/90

55 y or black:
CCB

Guideline

Population

Goal BP(mm
Hg)

Initial Drug
Treatment
Options

ADA
2013

Diabetes

<140/80

ACEI or ARB

A range of angiotensin II
receptor
blockers
(ARB)
is
available, and analyses suggest
there are differences between
agents in terms of
- antihypertensive
efficacy
- 24-hour BP control

Olmesartan vs Other AT1 Receptor

Blockers (ARBs)

Olmesartan:
An advancement in BP lowering effect of
ARB?
Though ARB is considered a modest
antihypertensive agent in terms of BP lowering
effect,
Olmesartan, the newest ARB in the market is
unique for its strong antihypertensive property
due to

What is different with Olmesartan?

Longer half life (13-15 hours)
Higher degree of receptor specificity(12500 fold
greater affinity to AT1 than AT2 receptor)

24 hour complete blockade of AT1 receptor due

to its unique chemical structure

Longer half life

Chemical Name

Olmesartan

Losartan

Half Life

13 hrs

6-9 hrs

AT 1 affinity
The specific AT1 affinity relates to how specificially attracted the medicine is for
the correct receptor.
1000 fold
Losartan

3000 fold
Telmisartan

8500 fold
Irbesartan

12500 fold
Olmesartan

olmesartan > candesartan > Irbesartan > telmisartan > losartan

* Andrew Whittaker .A Review of Olmesartan Medoxomil -- A New Angiotensin II Receptor Blocker . Br J Cardiol. 2005;12(2):125-129.

http://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonist#AT1_affinity

68

The need for truly 24 hours action including

the critical early morning hours
In most people BP displays a
characteristics diurnal pattern, with a
decline during sleep and sharp increase
around the time of awakening. It is due to
increase level of catecholamine in blood.
The early morning surge in BP is
synchronous with an increase in the risk of
catastrophic CV events, including
1. Acute MI
2. CV death &
3. Stroke.

Olmesartan significantly reduce BP in

the critical early morning hours
compare to other ARB

J Renin Angiotensin Aldosterone Syst2009; 10; 147 .Aug 3, 2009;

Olmesartan significantly reduce SBP &

DBP compared to other ARBs

J Renin Angiotensin Aldosterone Syst2009; 10; 147 .Aug 3, 2009;

These 3 benefits can result in strong

and sustained binding with AT1
receptor leading to truly 24 hours
action compared to other ARBs.

Prompt BP reduction compared

to Losartan after 2 weeks of
therapy

J Renin Angiotensin Aldosterone Syst 2009; 10; 147 .Aug 3, 2009;

Benefit beyond BP
lowering action of
Olmesartan

OLIVUS Trial

Prevention of

Atherosclerosis
progression is a striking
benefit of Olmesartan
over other ARBs beyond
powerful BP control

EUTOPIA Trial
Vascular Anti-inflammatory properties
of Olmesartan provides beneficial
cardiovascular effects in addition to its
BP lowering action

MORE Trial
Olmesartan is a
powerful ARB
that provides
prominent
Atherosclerotic
regression

VIOS Trial
Olmesartan

demonstrates
remodeling effects on
small resistance
blood vessel, offering
more complete endorgan protection

ROADMAP Trial
Olmesartan
reduces the
occurrence of
microalbuminuria
in patients with
type-2 diabetes,
even when BP
control is
excellent

Conclusion
Olmesartan is the most powerful AT1, receptor
blocker with highest degree of BP reduction.
It provides 24 hours BP control with a single dose.
Recorded side effects are minimal.
It provides cardiovascular protection in addition to
BP control.