Treatment-Resistant Hypertension: Management Approaches

Treatment-Resistant Hypertension:Management Approaches

Power Over Pressurewww.poweroverpressure.com

SBPDBP

BP treatment goals optimize CV risk reduction

mm Hg

<140Uncomplicated

hypertension

<80

<90

<130CKD

Diabetes

Chobanian AV, et al. Hypertension. 2003;42:1206-1252.Mancia G, et al. Eur Heart J. 2007;28:1462-1536


CV = cardiovascular; SBP = systolic blood pressure; DBP = diastolic blood pressure; CKD = chronic kidney disease.

Rationale for antihypertensive treatment: reduce CV risk

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s (%

)16

12

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6

4

2

0

14

2 4 6 8 10 12Time (Years)

Optimal (N=1005)<120/80 mm Hg

Normal (N=1059)120-129/80-84 mm Hg

High-Normal (N=903)130-139 / 85-89 mm Hg

Blood Pressure:

0

Impact of High-Normal Blood Pressure on Risk of Major Cardiovascular Events in

Men

Longitudinal data obtained from the Framingham Heart Study. Overall, those with high-normal BP had a 2-fold increase in relative risk for CV event compared with those with optimal BP levels (<120/80 mm Hg).Used with permission from: Vasan RS, et al. N Engl J Med. 2001;345:1291-1297.


BP level has a strong, continuous, and significant positive association with CV disease outcomes.

Despite advances in the treatment of hypertension….

Rauwolfia serpentina, Ganglion blockers, Veratrum alkaloids,

Hydralazine,Guanethidine,

Thiazide diuretics

Potassium thiocyanate,Kempner diet,

lumbodoral sympathectomy

1940s 1950 1960s 1970s 1980s 1990s 2000

α2-adrenergic-receptor agonists,

Spironolactone,β-adrenergic-receptor

antagonists

CCBs

ARBs

RIs

1. Chobanian AV. N Engl J Med. 2009;361:878-887.2. European Society of Hypertension History. ESH.

http://www.eshonline.org/About/ESHinBrief.aspx. Accessed July 27, 2011.3. Calhoun D, et al. Circulation. 2008;117:e510-e526.4. Egan BM, et al. Circulation. 2011;124:1046-1058

…the percentage of people with treatment-resistant hypertension

continues to increase3,4

1989

ESH formed

CCB = calcium channel blocker.ACEI = angiotensin-converting-enzyme inhibitor.ARB = angiotensin receptor blocker.RI = renin inhibitor.

20041,2

JNC 7 guidelines published

2003

ESH-ESC guidelines published

1985

ASH founded

1967

α2-adrenergic-receptor antagonists,

ACEIs

1st VA cooperative

study

1976

JNC 1 guidelines published


Mechanisms of action of major medication classes

1. Izzo JL, Black HR, Sica DA, eds. Hypertension Primer. 4th ed. 2008.2. Schlaich MP, et al. Hypertension. 2009;54:1195-1201.

Calcium-channel blockers

Centrally acting antihypertensives

β-blockers reset peripheral resistance

β -blockers

Baroreceptor discharge

α1-blockers

ARBs

ReninAngiotensinogen

Angiotensin I

Angiotensin II

Aldosterone

Thiazide

diuretics

ACEIs

β -blockers

Ca2+

AT

α1

Vascular smooth muscle

Peripheral resistance

Na+

Vasodilation

Any medication that causes a sustained reduction in BP must reset the renal threshold for pressure naturesis to a lower pressure level, either directly or indirectlyMultiple available therapies target RAAS, thereby inhibiting the effects of SNS activity1,2

• ACEIsDecrease production of angiotensin II

• ARBsBind and block the angiotensin AT1 receptor

• DRIsDirectly inhibit renin

• β-blockersReduce renin release

• DiureticsInhibit water and sodium retention

RAAS = renin-angiotensin-aldosterone system; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; DRI = direct renin inhibitor.


Mechanisms of action of major medication classes (cont)

• CCBsDilate arteries and reduce peripheral resistance

• α-blockersBlock vasoconstrictor effects of NE

• Centrally acting agentsAct on the hypothalamus to reduce sympathetic outflow

Izzo JL, Black HR, Sica DA, eds. Hypertension Primer. 4th ed. 2008.

CCBs

Centrally acting antihypertensives

β-blockers reset peripheral resistance

β -blockers

Baroreceptor discharge

α1-blockers

ARBs

ReninAngiotensinogen

Angiotensin I

Angiotensin II

Aldosterone

Thiazide

diuretics

ACEIs

β -blockers

Ca2+

AT

α1

Vascular smooth muscle

Peripheral resistance

Na+

Vasodilation

NE = norepinephrine.Power Over Pressure

www.poweroverpressure.com

Combinations of drugs with complementary mechanisms of action improve efficacy and reduce side effects

*Not proven beneficial in controlled trials. Reproduced with permission from Mancia G, et al. Eur Heart J. 2007;28:1462-1536.

Diuretics

-blockers*

-blockers ARBs

CCBs

ACEIs

Solid lines indicate preferred combinations.


Optimizing combination therapy

• An effective treatment regimen should target multiple mechanisms responsible for BP control1– While 3-drug combinations have not been

extensively studied, the combination of an ACE inhibitor or ARB, a CCB, and a thiazide-like diuretic is effective and well-tolerated2

• If BP control is not achieved, dosages should be titrated to the maximum tolerated or in-label doses1,2

1. Moser M, Setaro J. N Eng J Med. 2006;355:385-392.2. Calhoun D, Jones D, Textor S, et al. Circulation. 2008;117:e510-e526.


Spironolactone

• Design: Uncontrolled extension of the ASCOT trial

• Patients who did not achieve BP control on their assigned 3-drug regimen had additional agents added at investigator’s discretion

• Population: 1411 patients prescribed spironolactone for HTN in addition to their trial-assigned regimen

• Treatment: spironolactone 25 mg once daily (median dose)

• Results: With the addition of spironolactone, mean BP fell by 21.9/9.5 mm Hg (P<0.001).

Chapman N, et al. Hypertension. 2007;49:839-845.

Spironolactone can be effective in many patients with treatment-resistant hypertension


• Adverse events*: Experienced by 13% of patients. Gynecomastia (6%) and biochemical abnormalities (2%), mainly hyperkalemia, were most frequent

*Among trial participants prescribed spironolactone for any reason.

Please see product Prescribing Information for complete information about adverse events.

Referral to hypertension specialists

Patients with treatment-resistant hypertension who are motivated to work with a hypertension specialist may benefit from referral

1. Bansal N, et al. Am J Hypertens. 2003;16:878-880.2. Garg JP, et al. Am J Hypertens. 2005;18:619-626.

• A retrospective study found that patients with treatment-resistant hypertension achieved an 18/9 mm Hg drop in BP and control rates increased from 18% to 52% at 1-year follow-up1

• In another retrospective study, 53% of patients with treatment-resistant hypertension were controlled to BP target (<140/90 mm Hg)2


• The SNS connects the brain, heart, blood vessels, and kidneys, each of which plays an important role in the regulation of BP

• Signals from the SNS produce a baseline sympathetic tone, which when elevated contributes to the development and progression of disease states including hypertension

Promising treatments are based on a new appreciation for the role of the sympathetic nervous system (SNS)

Campbell WW. The Autonomic and Peripheral Nervous Systems. In: Campbell, WW, editor. DeJong’s The Neurologic Examination: Incorporating the Fundamentals of Neuroanatomy and Neurophysiology. 6th ed. Philadelphia, PA: Lippincott Williams and Wilkins;2005 p. 535-547.

Epinephrine—adrenal glandsNorepinephrine—kidney

Inhibits digestive activity

Stimulates glucose release by liver

Dilates pupils

Inhibits salivation

Relaxes bronchi

Accelerates heart

Relaxes bladder

Contracts rectum

Cer

vica

lTh

orac

icLu

mba

r


Renal denervation as a therapeutic approach

Schlaich MP, et al. Hypertension. 2009;54:1195-1201.

• Renal afferent and efferent sympathetic nerves are key players in the feedback loop of sympathetic hyperactivity associated with hypertension


Renal denervation as a therapeutic approach

Schlaich MP, et al. Hypertension. 2009;54:1195-1201.

• Renal denervation, an investigational* therapy, is a minimally invasive, catheter-based procedure that modulates the output of nerves lying within the renal artery wall, leading into and out of the kidneys

• Renal sympathetic denervation involves selectively disabling renal nerves within the SNS, thus impacting the mechanical and hormonal activities of the kidneys, as well as the electrical activation of the rest of the SNS


*Device based approaches such as renal denervation and baroreceptor stimulation are not universally approved for use, and are under clinical investigation in some regions (such as the US and Japan).

Baroreflex activation therapy as a therapeutic approach

1. Bisognano JD, et al. J Am Coll Cardiol. 2011;58:765-773.2. Heusser K, et al. Hypertension. 2010;55:619-626.3. Wustmann K, et al. Hypertension. 2009;54:530-536

• Baroreceptor stimulation is an investigational* therapeutic approach that treats hypertension by modulating sympathetic nerve activity1

• Using a system similar to a pacemaker that is surgically and permanently implanted, the therapy is administered via electrical stimulation of the carotid baroreceptors

• Therapy attempts to normalize sympathovagal imbalance by reducing the activity of the SNS2 while increasing parasympathetic activity3


*Device based approaches such as renal denervation and baroreceptor stimulation are not universally approved for use, and are under clinical investigation in some regions (such as the US and Japan).

Summary: management of treatment-resistant hypertension• Target BP goals should be adjusted in patients with

diabetes or CKD to optimize CV risk reduction• Elevated BP has long-term CV consequences• Although several classes of drugs exist, the percentage

of people with treatment-resistant hypertension continues to rise

• Combination therapy, including the use of spironolactone, may improve efficacy and reduce side effects

• Referral to a hypertension specialist may prove beneficial• Investigational treatments based on a new appreciation

for the role of the SNS are being developed Power Over Pressurewww.poweroverpressure.com

Treatment-Resistant Hypertension: Management Approaches

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