Lady DavisInstitute

Resistant hypertension

Ernesto L. Schiffrin CM, MD, PhD, FRSC, FRCPC

Physician-in-Chief, Sir Mortimer B. Davis-Jewish General Hospital, Canada Research Chair in

Hypertension and Vascular Research, Lady Davis Institute for Medical Research,

Vice-Chair, Department of Medicine, McGill University, Montreal, PQ, Canada.

Vital

signs: prevalence,treatment, and control of

HTNUnited

States,1999-2002

and 2005-2008

Center for Disease Control and Prevention (CDC)MMWR Morb Mortal 2011;60:103-108.

Prevalence

of resistant hypertension in the United States,

2003-2008(averag

eof2 out3 measuresby a physicia

n)

Persell SD.

Hypertension 2011; 57: 1076-1080.

Resistant vs refractory hypertensionResistant hypertension is hypertension that doesrespond to adequate doses of 3-4 or moreantihypertensive drugs.It represents 10-15% of the general hypertensive population.Refractory hypertension is defined as BP that

not

remains uncontrolled after 3 visits to a hypertensionclinic within a minimum 6-month follow-up period.Secondary causes of hypertension, obesity, diabetes, sleep disordered breathing and excess salt intake or use of AINS drugs are among some of the findings associated with resistant or refractory hypertension.

Clinical features of 8295 patients with resistant

hypertension classified on the basis of ABPM• Prevalence of resistant hypertension in the

Spanish ABPMregistry• Resistance defined by BP in office ≥140/90 mmHg andantihypertensive drugs

≥ 3

•••

12.2% of 68,045After ABPM: 62.5% wereAfter ABPM :55.9%

true resistant ≥130/80 mmHg

≥135/85 mmHg

• Selected population

Calhoun DA et al. Hypertension 2008

Calhoun DA et al. Hypertension 2008

Calhoun DA et al. Hypertension 2008

Calhoun DA et al. Hypertension 2008

Endothelial

dysfunction

inresistant

hypertension

Quinaglia T et al. Journal of Human Hypertension doi:10.1038/jhh.2011.43

Non dipping

pattern

inresistant

hypertension

Quinaglia T et al. Journal of Human Hypertension doi:10.1038/jhh.2011.43

Resistant hypertension with or withoutcerebr

almicroangiopathy

Schmieder RA et al. J Clin Hypertens.

2011;13:582–587.

How to approach resistant hypertension

The general treatment approach:

1.adding or titrating diuretic therapy,2.changing the diuretic class to one appropriate for the patient’s kidney function,3.using medications with complementary mechanisms of action, and4.adding a mineralocorticoid antagonist to the antihypertensivedrug regimen.

How to approach resistant hypertension

1.

RAS blocker + diuretic + CCB + MR antagonist with or withouta beta-blockerThiazide diuretics: chlorthalidone @ 25 mg⁄ d, preferred formost patients.CKD: loop diuretic, most commonly furosemide at 20 mg to40 mg twice daily.

Vasodilators, centrally acting antihypertensive agents, and alpha-adrenergic blockers added if failure to control BP.

2.

3.

4.

How to approach resistant HTN

•Adherence needs to be assessed by asking thepatient about medication use, perceptionsabout medication efficacy, and presence ofadverse effects, if any.Patients must be seen every 4 to 8 weeks, with more frequent visits for patients with uncontrolled BP.

•

Resistant HTN treatment

•Use of a MR antagonist in addition to adiuretic, particularly chlorthalidone, inaddition to a full dose of a RAS blocker and aCCB is usually associated with control rates ofresistant hypertension >80%.

Spironolactonein Patients WithResistantArterialHypertension(ASPIRANT)

Václavík J et al.Hypertension.2011;57:1069-1075.

Spironolactone

inResistant

Hypertension

Václavík J et al. Hypertension. 2011;57:1069-1075.

Refractory hypertension

Acelajado MC et al. J Clin Hypert

2012;14:7–12

Refractory

hypertension

Acelajado MC et al. J Clin Hypert

2012;14:7–12

Refractory

hypertension

Acelajado MC et al. J Clin Hypert

2012;14:7–12

Response

to MR antagonist

Acelajado MC et al. J Clin Hypert

2012;14:7–12

Refractory hypertension: mechanisms

•No evidence of greater fluid retention inrefractory HTN vs controlled resistant HTNsince aldosterone or PRA levels notsuppressedGreater role of increased cardiac output and

• ⁄or vascular resistance: enhanced sympatheticdrive and ⁄ or increased peripheral resistancesecondary to local or circulating pressoragents?

Acelajado MC et al. J Clin Hypert 2012;14:7–12

BP response to treatment with ETA antagonistcompared toguanfacin

eChangeinsiSBP

Change in ASBP

Change in ADBP

Bakris G L et al.Hypertension 2010;56:824-830.

ASBP over 24h

Figure 2. Mean change from baseline in sitting systolic BP over time. Observed values at each timepoint are displayed.

New approaches to refractory HTN

• Catheter-Based Radiofrequency RenalSympathetic Denervation• Baroreceptor stimulation

Catheter-Based Radiofrequency Ablation

ofRena

lSympathetic

Nerves

The SYMPLICITY-HTN results showed that

six months

after theablation, average office BP in the renal-

denervation group wasreduced by 32/12 mm Hg (average baseline 178/96 mm Hg), whereas it did not differ from baseline in the control group. Between-group differences in BP at six months were 33/11 mm Hg (p<0.0001).

Renal sympathetic denervation in patients with treatment-

resistant hypertension (The Symplicity HTN-2 Trial): a

randomised controlled trial

Simplicity HTN- 2 investigators ( Murray D Esler) Lancet

376;1903-1909

2010:

Objective: Activation of the sympathetic renal system is

involved in the pathogenesis of hypertensionRCT in patients wint BP>150 mmHg taking

3 drugs:denervation + Rx or Rx

aloneMeasured systolic BP at 6 monthsProcedures: Catheter SYMPLICITY in renal arteries

renal

4-6 low-intensity stimulations on the renal artery

BP 178/97 mmHg in patients 57-year old (male=60%) taking mean of 5.2 drugs (35% more than 5 )

a

SymplicityHTN-2 Tri

al

The Lancet 2010;376: 1903-1909

Symplicity HTN-1 Investigators

Catheter-Based Renal Sympathetic Denervation for Resistant Hypertension:Durability of Blood Pressure Reduction Out to 24 Months153 patients with catheter-based renal sympathetic denervation at 19 centersHypertension. 2011;57:911-917.

BP changes after renal sympathetic denervationove

r24-months

of

follow-up

Krum H. et al. Hypertension. 2011;57:911-917.

Randomized controlled clinical trials

SimplicityHTN 3

DEPART ReSET MIRT DENER- HTN

PRAGUE-15 INSPIRE

Recruiting Y Y Y Y Y Y N

Intervention

RDN RDN RDN PVI+RDN RDN RDN RDN

No. patients

530 120 70 150 120 150 230

Catheter Simplicity

Simplicity

Simplicity

THERMOCOOL Simplicity

Simplicity

TBD

Completion 2013

2014

2012

2012

2014 2013

2016

Country USA Belgium Denmark Russia France Czech Rep.

Europe

Renal function

mGFR/cys C

eGFR/mGFR

Imaging renal arteries

Arteriogr (6) AngioCT (12,24, 36)

Center

requirements for application

of

RDN inrefracto

ryHTN

Modified from Joint UK Societies Consensus on RDN for treatment-resistant HTN

Experience Management of resistant hypertensionHigh volume interventional cardiology/radiologyProtocol Written protocol for work-up, procedure & f/u Written informed consent and ethics approval Plans for management of complications

Infrastructure

High quality CT/MRI Hemodynamics labMultidiscip

linary team

HTN specialists experienced in managing resistant HTN Interventional cardiologists/radiologists experienced in RDN and nephrologists and vascular surgeons

Transparency Participation in registration program

Carotid Baroreceptor Stimulation, Sympathetic activity, Baroreflexfunctio

nand Bloodpressur

einHypertensive

Patients

Heusser K et al. Hypertension 2010;55:619-626

Conclusion

Diagnosis, including ABPM

•••••

Exclude secondary causes3 drugs (RAS inhibitor, CCB,

diuretic)

+ MR blocker

Adherence to treatment, salt intakeF/u and only then consider invasive treatments

Gracias