resistance htn & acei vs arb

Resistant Hypertension

Use of Anti hypertensive – ARB/ACEI Issues

© 2008, American Heart Association. All rights reserved.

• 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.

What is Resistant Hypertension

BP not on target

Three drugs used

One is a diuretic

At optimal dosage

In Compliant Patient

On life style change

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.

Definition Highlights

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;52:1749–57

Resistant HT: Introduction (Contd)

• Patients with resistant HT may achieve BP control with full doses of– 4 or more antihypertensive

medications



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

1Hajjar I, Kotchen TA. JAMA 2003; 2Peralta CA et al. Hypertension 2005; 3Cushman WC et al. Clin Hypertens.

Drug-relatedcauses58%

Nonadherence16%

Unknown6%

Officeresistance

6%

Psychologicalcauses

9%

SecondaryHTN5%

Interferingsubstances

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

• Factors include– Suboptimal BP measurement

technique; – The white-coat effect; and – Poor adherence to prescribed therapy


Pseudo-resistance (Contd)


Causes of Pseudo-Resistant Hypertension

Factors Contributing to Resistant HT



Causes of Resistance to Hypertension Treatment

• Poor adherence with prescribed medications • Inaccurate blood pressure measurement

• White coat hypertension


• 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

Substances that Can Interfere with Blood Pressure Control


Substances that Can Interfere with Blood Pressure Control

• Alcohol

• Oral contraceptives

• Cyclosporine

• Erythropoietin

• Natural licorice

• Herbal compounds -ephedra - ma huang


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


Evaluation of Resistant Hypertension

• Confirm appropriate treatment

• Identify causes- Secondary?

• Document target organ damage


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


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


• 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)


Treatment of Resistant HypertensionNon-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


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


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)

Journal of Human Hypertension 2004;18:139–185

•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 long-acting 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


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 used conventionally

Journal of Human Hypertension 2004;18:139–185

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


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

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 retention

Direct Vasodilators (Contd)

•Minoxidil

– 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

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

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<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

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


• 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


• The development of this novel catheter-based 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


• 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

• ■ 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.

Facts

•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 ARB’s

Losartan1986Valsartan,

Candesartan Irbesartan

1990 Telmisartan1991 Olmesartan1995

Became the first successful Ang II antagonist drug

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

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

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

Guideline

Population

Goal BP(mm Hg)

Initial Drug Treatment Options

JNC 8 ≥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

ARB according to Guideline

Guideline Population Goal BP(mm Hg)


ESH/ESC 2013

General nonelderly

<140/90 β-Blocker, diuretic, CCB, ACEI, or ARB

General elderly <80 y

<150/90 β-Blocker, diuretic, CCB, ACEI, or ARB

General ≥80 y <150/90 β-Blocker, diuretic, CCB, ACEI, or ARB

Diabetes <140/85 ACEI or ARB

CKD no proteinuria

<140/90 ACEI or ARB

CKD + proteinuria

<130/90



NICE 2011

General <80 y <140/90 <55 y: ACEI or ARB

General ≥80 y <150/90 ≥55 y or black: CCB



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

1000 fold• Losartan

3000 fold• Telmisartan

8500 fold• Irbesartan

12500 fold• Olmesartan

68

The specific AT1 affinity relates to how specificially attracted the medicine is for the correct receptor.

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

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.

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.

The need for truly 24 hours action including the critical early morning hours

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 ARB’s

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

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

OLIVUS Trial

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

“Olmesartan demonstrates remodeling effects on small resistance blood vessel, offering more complete end-organ protection”

VIOS Trial

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

ROADMAP Trial

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.

resistance htn & acei vs arb

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