diagnosis & management of resistant hypertension -...

Diagnosis & Management of

Resistant Hypertension

Dr.Vinod Sharma

National Heart Institute

New Delhi

“As we enter the third millennium,

we are on the verge of the

biggest epidemic of cardiovascular

disease in human history,

most of it blood pressure related”

Hypertension in India

PREVALENCE

Urban Adults 25%

Rural Adults 10-15%

JAPI Feb 2013

Hypertension – Rule of Halves

Only ½ have been diagnosed.

Only ½ of those diagnosed have been treated.

Only ½ of those treated are adequately

controlled.

Thus only 12.5% overall are adequately

controlled.

1999 WHO – ISH Guidelines

• 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.


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.

Resistant HT: Introduction

This definition does not apply to patients who have been

recently diagnosed with HT

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;52:1749–57

Prevalence (contd)

• ACCOMPLISH (Avoiding Cardiovascular events through

Combination therapy in Patients Living with Systolic

Hypertension) Study – 25 to 28% of subjects remained

uncontrolled in spite of intensification of treatment.

Circulation 2012: 125: 1594-96

Resistant hypertension is primarily a

systolic and age related problem

• Diastolic BP goal achieved ≥ 90% in the

major trials

• Systolic BP goal achieved 60-65% in the

major trials

• True resistance occurs in about 15%

Drug-related causes

58%

Nonadherence 16%

Unknown 6%

Office resistance

6%

Psychological causes

9%

Secondary HTN 5%

Interfering substances

1%

Am J Hypertens 2003;16:925-930

Cause of resistance

found in 133/141 –

94% (83/91 – 91%)

cases

Resistant HT: Primary Cause

Pseudo-resistance

Lack of BP control with

appropriate treatment in a

patient who does not have

resistant hypertension


Pseudo-resistance (Contd)


Causes of Pseudo-Resistant Hypertension

Resistant HT

Factors Contributing to

Resistant HT


Common

• Obstructive sleep apnea

• Renal parenchymal disease

• Primary aldosteronism

• Renal artery stenosis

Secondary Causes of Resistant

Hypertension

Secondary Causes of Resistant Hypertension

Uncommon

Pheochromocytoma

Cushing’s disease

Hyperparathyroidism

Aortic coarctation

Intracranial tumor

RHTN & Obstructive Sleep Apnoea

Prevalence – Men 24%; Women 9% (Wisconsin Sleep

Cohort Study)

High prevalence of RHTN in OSA (n = 41); 96% men,

65% women (apnea – hyperapnoea Index > 10)

Mechanism

- Increased sympathetic activity

- Increased Aldosterone levels

- Increase in reactive oxygen species with

concomitant reductions in nitric oxide bioavailability.


A BP increase during progressive stages of sleep.

Significant correlation between Aldosterone level &

severity of OSA.

Chronic parapharyngeal fluid retention mediated by

aldosterone excess and nocturnal rostral fluid shift from

lower extremities contributes to the worsening airways

resistance in OSA.


“The hypothesis of Aldosterone excess worsening

severity of OSA is supported by a prospective study

showing a reduction in severity after 8 weeks of treatment

with spironolactone in patient with RHTN & Obstructive

Sleep apnea”.

J Hum Hypertens 2010

RHTN & Aldosterone

Prevalence of primary hyperaldosteronism in patients

with RHTN 11 – 20% Lancet 2008: 371

Compared to Conn’s syndrome, picture of biochemically

confirmed primary hyperaldosteronism remains diverse:

- shows negative imaging

- remains Idiopathic

- hypokalemia is usually a late manifestation

- normokalemia is quite common among these

patients

J. Clin Endocrinol Metab 2009

RHTN & Renal Artery Stenosis

Renovascular disease ( >70% stenosis) found in more

than 20% cases undergoing CAG.

Role of such lesion in causation of hypertension is

unknown.

> 90% RAs are atherosclerotic (elderly male), < 10% are

due to FMD (F, <50 yrs of age).

Large experience with both surgical and endovascular

revascularization indicates that some patients with

renovascular hypertension experienced improved BP

control although RCT in general have not shown

convincing benefit in regard to improvement in renal

function or BP control.

Renal Artery Stenosis: Investigation

Screening

Ultrasound, Doppler

Renogram /scintigraphy

Peripheral PRA

Definitive

CT angio, MRA, DSA

Conventional angio

Renal vein renin ratio

Resistant HT (Contd)

How to evaluate & manage

with Patients Appearing to

Have Resistant HT?


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

Modification Approximate SBP

Reduction

Weight Reduction 5-10 mmHg/10kg

Adopt DASH eating plan 8-14 mmHg

Dietary sodium reduction 2-8 mmHg

Physical activity 4-9 mmHg

Moderation of alcohol intake 2–4 mmHg

Lifestyle Modifications….. help

•Non-steroidal anti-inflammatory agents

•Sympathomimetics

- Diet pills

- Decongestants

•Stimulants

•Oral contraceptives

•Licorice

•Ephedra

Discontinue or Minimize Interfering Substances

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)

• Cushing’s disease (moon facies, central obesity, abdominal striae,

inter-scapular fat deposition)

• Aortic coarctation (differential in brachial or femoral pulses, systolic

bruit)


Constructing a potent Antihypertensive

Regimen


Do not accept blood pressure that are not at

target: there are still things that can be done.

Revisit the initial regimen and ensure optimal

dosed drug & combination.


Do not keep Adding medications

- appropriate & optimally dosed 3 drug regimen

should suffice for BP control.

- adding multiple additional drug has potential for

serious side effects.

- attempt to find an underlying cause & tailoring

treatment for that cause is necessary.

RHTN – Constructing an effective

antihypertensive regimen

Are dose titrations appropriate?

E.g. Carvedilol should be maximized to

25-50 mg twice a day.

Low dose diuretics 12.5 mg HCTZ will not

work in chronic renal disease and may

have a substandard effect in others.

Resistant Hypertension – Constructing a

potent antihypertensive regimen

Adding a complementary agent from another class of

antihypertensives may be superior to “maxing out” single agent

first.

Doubling the dose of one drug (or monotherapy) had

approximately one-fifth of the equivalent incremental blood

pressure lowering effect of adding another drug class before trying

to max-out.

CAVEATS: 50 mg HCTZ or combination Diuretics.

Wald DS et al: Combination treatment Vs Monotherapy in

reducing blood pressure: a meta-analysis on 11,000 participants in

42 trials. Am J Med 2009: 122: 290


Perform a “Diuretic Review”.

Diuretics is the mainstay of the resistant

hypertension patient medication regimen &

should be optimized to see full therapeutic

benefit.

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 long-acting

thiazide diuretic will be most effective

Circulation. 2008;117:e510-e526

Resistant Hypertension – Diuretic Review

Chlorthalidone may give more “bang for the buck” than HCTZ.

- Chlorthalidone is more patent than HCTZ (50mg HTCZ = 25 –

37 mg CHTD).

- It has longer duration of action (16 – 24 hrs Vs 48-72 hrs)

- Gives better lowering of BP

- 1 month of chlorthalidone use translates into 1 day of additional

life.

- 23 year follow up of Cohort – Chlorthalidone can be a “gift that

keeps on giving”.

Resistant Hypertension – Diuretic Review

Thiazide Diuretic may lack effect at lower GFR (Stage 3

Kidney disease).

Frusemide may a better option than thiazide for BP

control.

Because of shorter half life, Frusemide may be dosed

twice.


Is Patient taking Betablockers?

Resistant Hypertension - Betablockers

Betablockers are no longer acceptable first line

therapies, unless there are compelling indications like

CAD, CHF etc. &

One agent specifically Atenolol may increase central

aortic pressure Central Study, J Clin Hypert 2011

Switch to a optimal dose of dual acting Beta blocker

(Carvedilol or Labetalol).

- additional lowering of BP due to ∞ blockade.

- better LV / Vascular coupling

- carvedilol does not increase Insulin resistance.

RHTN – Constructing a antihypertensive

regimen

Antihypertensives at night

“When you snooze you lose”

Controlling BP in chronic renal disease

“Night time is the right time”

Rutecki GW. Consultant Live 2011

Use a long half life agent at night rather

than in the morning.

α1-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

RHTN – Constructing an effective


The Use of last line agents viz. Clonidine

lacks outcome data and may add adverse

drug reaction & decreased adherence

because of dosing frequency.

RHTN – Constructing a potent


Question the value of Hydralazine

Hydralazine does not have much

evidence of efficacy for prevention of

cardiovascular benefit when used for

essential hypertension.

Cochrane Database Syst Rev 2011

RHTN – Constructing a potent


MINOXIDIL Should be a last Resort

Potent vasodilator and should be used with betablocker

& diuretics.

Difficult to use & fraught with many serious side effects

(Edema, anasarca, pericardial effusion & hirsutism).

Can be used for select patients by physicians who are

comfortable with dosing & side effects

J Hyperten 2007

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 added to existing multidrug regimens

Circulation. 2008;117:e510-e526

RHTN – Constructing an optimal


Switch to a regimen relying on a

spironolactone backbone.

Multiple studies attested efficacy of

spironolactone in patients with RHTN, especially

those with OSA.

Dose of spironolactone may be titrated

upwards, needs serial K+ monitoring especially

in CKD.

J Hum Hypertens 2012

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

Not when creatinine > 2.5, K > 5.0

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

RHTN – Optimal Antihypertensive Regimen

Preferred Antihypertensive Combinations

A RAAS inhibitor & a Calcium Channel Blocker

A RAAS inhibitor & a Diuretics (especially a

thiazide)

A RAAS inhibitor & a Calcium Channel Blocker

plus a Diuretic

Eur Heart J: 2011: 32

RHTN – Optimal Antihypertensive Regimen

Acceptable Combinations

Betablockers & Diuretics

Calcium Channel Blockers & Diuretics

Dual Calcium Channel Blockade (DHP & NDHP agent)

Unacceptable Combinations

Dual RAAS blockade

RAAS inhibitors plus betablockade

Betablockers plus antiadrenergic drugs

Eur Heart J 2011

Diagrammatic representation of L/N-dual action

of cilnidipine

Efferent arterioles Afferent arterioles

Newer therapeutic agent

Endothellin antagonist: Darusentan

ACEI/ ARB + naprilysin inhibitor : LCZ 696

Aldosternone synthase inhibitors: Fadrozole, LCI 1699

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 (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<0·0001 for all effects)

Lancet 2009; 374:1423-1431

Darusentan (Contd)

Results (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 cardiac-related 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

Interventional Management of


CORAL (Cardiovascular Outcomes in

Renal Atherosclerotic Lesions) TRIAL 2013

STENTS NO BENEFIT IN RENAL ARTERY

STENOSIS

“Effective Medical Therapy should be the first line of

treatment in patients with presumed Renovascular

Hypertension”. For patients who fail medical therapy or

are unable to tolerate medical therapy, stenting remains

a reasonable option.

NEJM 2013

RHTN – Renal Denervation Therapy (RDN)

RDN is a use of low energy radiofrequency

delivered via a percutaneously inserted catheter

for the bilateral disruption of afferent & efferent

sympathetic nerves in the adventitia of renal

arteries.

Renal Nerves: Key Contributor in HTN

Efferent Sympathetic Activation Afferent Sympathetic Activation

HR Vasoconstriction Contractility

RBF/GFR Renin

Na+/Volume

Patients cannot develop and/or maintain The kidney is a source of central elevated BP without renal involvement sympathetic drive in hypertension

Anatomical Location of Renal

Sympathetic Nerves

• Arise from T10-L1

• Follow the renal artery to the kidney

• Primarily lie within the adventitia

Vessel

Lumen

Media

Adventitia

Renal

Nerves

RHTN – Renal Denervation Therapy Simplicity HTN – 1

Multi-centre, proof-of-principle study to demonstrate feasibility,

efficacy & safety of RDN in patients with RHTN.

N = 45, Mean BP 177 / 101 mm Hg; Mean of 4.7 Antihypertensive

drugs.

BP reduction – 21/11 mm Hg at 6 months

27/17 mm Hg at 12 months

32/14 mm Hg at 24 months

Decrease in LV mass of 9%

----------------------------------------------------------------------------------------------

Encouraging result

Did not include a control group & was not a blinded study.

Placebo effect could not be excluded.

NEJM 2009

RHTN – Renal Denervation Therapy

Simplicity HTN - 2

Multicentre, Randomized Control, trial in 106 patients

BP reduction – 32 / 12 – 6 months

Similar at 12 months

------------------------------------------------------------------------------

Non-blinded Study

SIMPLICITY HTN – 3 ONGOING

LANCET 2010

Carotid sinus stimulation with device

Electrode implanted on both carotid sinuses

The adventia is stimulated directly.

Pacing electrodes pad placement close to the carotid bifurcation.

Carotid sinus stimulation with device

. Dinamap B.P. during a hypertensive crisis

Fall of B.P. Systolic B.P. >45 mm Hg, and diastolic 50 mm Hg.

Device was shut off, B.P. increased over 4 hours. Continuation

stimulus resulted in B.P. level to the previous stimulation .

Rheos Device

Promising new technology

May help those difficult to control

patients in combination with drug

therapy

May be useful in non compliant patients

May be useful in patients intolerant to

medication

RHTN – Diagnosis & Management CONCLUSION

RHTN, a common problem, in a subset of patients.

Pseudo resistance needs to be rules out.

ABPM a very helpful tool.

Secondary causes must be rules out & treated appropriately.

Judicious up-titration of single / or appropriate combination of

drugs overcomes this problem.

Diuretics, cornerstone of therapy of RHTN.

Stenting Renal artery in RAS, does not help much.

Newer drugs & interventions holds promise for the future.

THANK YOU

diagnosis & management of resistant hypertension -...

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