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 2003421206 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 200852174957
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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 200852174957
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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 2005231441 4.
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Resistant HT Primary Cause
Cause of resistance found in 133/141 94 (83/91
91) cases
Am J Hypertens 200316925-930
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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 200852174957
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Pseudo-resistance (Contd)
Causes of Pseudo-Resistant Hypertension
J Am Coll Cardiol 200852174957
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Resistant HT
Factors Contributing to Resistant HT
J Am Coll Cardiol 200852174957
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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 200852174957
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J Am Coll Cardiol 200852174957
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Journal of Human Hypertension 200418139185
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Compelling and possible indications,
contraindications and cautions for the major
classes of antiHT drugs
Journal of Human Hypertension 200418139185
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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. 2008117e510-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. 2008117e510-e526
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Diuretics (Contd)

• In patients with oedema or more advance renal
  impairment, for example, serum creatinine gt200
  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 200418139185
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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. 2008117e510-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 gt 2.5, K gt 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 200954951-953
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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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a1-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) 20079760 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 3741423-1431
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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
  (plt00001 for all effects)

Lancet 2009 3741423-1431
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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 3741423-1431
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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 3741423-1431
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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. 2009373(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. 2009373(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. 2009373(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,542009 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,542009 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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Thank You!