Recent advances in the management of resistant hypertension.
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Transcript of Recent advances in the management of resistant hypertension.
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Recent advances in the management of resistant hypertension
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Scope
Resistant hypertension Introduction Prevalence Management
Additional drug/combinations Newer therapies Conclusions
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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.
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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
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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;52:1749–57
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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.
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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
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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;52:1749–57
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Pseudo-resistance (Contd)
J Am Coll Cardiol 2008;52:1749–57
Causes of Pseudo-Resistant Hypertension
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Resistant HT
Factors Contributing to Resistant HT
J Am Coll Cardiol 2008;52:1749–57
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Resistant HT (Contd)
Step-by-Step Physician Guide for Evaluation and Management of Patients Appearing to Have Resistant HT
J Am Coll Cardiol 2008;52:1749–57
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J Am Coll Cardiol 2008;52:1749–57
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Journal of Human Hypertension 2004;18:139–185
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Compelling and possible indications, contraindications and cautions for the major classes of antiHT drugs
Journal of Human Hypertension 2004;18:139–185
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What additional agents to add?
What combinations work?
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Resistant HT: Newer approaches
Under evaluation Endothelial receptor antagonist Catheter-based renal sympathetic
denervation
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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Catheter-based renal sympathetic denervation (Contd)
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
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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
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Conclusions
Resistant HT is common in nephrology clinics
4 or more drugs may be used for management
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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
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Conclusions
Newer therapies like catheter-based renal sympathetic denervation, darusentan are under evaluation
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