Download 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
J Am Coll Cardiol 2008;52:1749–57
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.
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;52:1749–57
Pseudo-resistance
(Contd)
Causes of Pseudo-Resistant Hypertension
J Am Coll Cardiol 2008;52:1749–57
Resistant HT
Factors Contributing to
Resistant HT
J Am Coll Cardiol 2008;52:1749–57
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
J Am Coll Cardiol 2008;52:1749–57
Journal of Human Hypertension 2004;18:139–185
Compelling and possible indications, contraindications
and cautions for the major classes of antiHT drugs
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
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 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
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

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

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
(Contd)
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
 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 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
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
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