recent advances in the management of resistant hypertension

Recent advances in the management of resistant hypertension

Scope

Resistant hypertension Introduction Prevalence Management

Additional drug/combinations Newer therapies Conclusions

Resistant HT

The Joint National Committee 7 defines resistant hypertension as Failure to achieve goal BP (140/90 mm Hg

for the overall population and 130/80 mm Hg for those with diabetes mellitus or chronic kidney disease) when a patient adheres to maximum tolerated doses of 3 antihypertensive drugs including a diuretic

Hypertension 2003;42:1206 –52.

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


Resistant HT: Prevalence

The prevalence of resistant HT in the general population is unknown

Small studies, however, demonstrate a prevalence of resistant HT that ranges from approx.

5% in general medical practice to 50% in nephrology clinics

J Hypertens 2005;23:1441– 4.

Drug-relatedcauses

58%

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

Resistant HT

Factors Contributing to Resistant HT


Resistant HT (Contd)

Step-by-Step Physician Guide for Evaluation and Management of Patients Appearing to Have Resistant HT


Journal of Human Hypertension 2004;18:139–185

Compelling and possible indications, contraindications and cautions for the major classes of antiHT drugs


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


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

Conclusions

Resistant HT is common in nephrology clinics

4 or more drugs may be used for management

Conclusions: Summary of Med Changes

Use chlorthalidone 25mg Add spironolactone 12.5 – 50 mg Consider adding hydralazine or minoxidil Consider alpha1-blocking agents,and

combination alpha-beta blockers Loop diuretic (eg furosemide) may be

required, often in higher doses than used conventionally

Conclusions

Newer therapies like catheter-based renal sympathetic denervation, darusentan are under evaluation

recent advances in the management of resistant hypertension

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