Resistant and Refractory Hypertension: Antihypertensive

Treatment Resistance vs. Treatment Failure

David A. Calhoun, M.D.Vascular Biology and Hypertension

ProgramUniversity of Alabama at Birmingham

Presenter Disclosure

Grant Support: NIH, AHA

Consultant: Valencia Technologies

Clinical Trails Medtronic

• Resistant hypertension is defined as blood pressure that remains above goal in spite of concurrent use of 3 antihypertensive agents of different classes.

• Ideally, one of the 3 agents should be a diuretic and all agents should be prescribed at optimal dose amounts.

• Controlled resistant hypertension: patients whose blood pressure is controlled with use of more than 3 medications.

Definition

AHA Scientific Statement Hypertension 2008

8.8%

14.5%

20.7%

Prevalence of Resistant Hypertension in USNHANES 1988-2008

Roberie and Elliot, Curr Opinion Cardiol 2012

Risk Factors for Having Resistant HypertensionKaiser-Permanente Southern California

470,386 Hypertensives60,327 Resistant

Sim et al., Mayo Clinic Proceedings 2013

Apparent vs. True Resistant Hypertension

RESISTANT HYPERTENSION

UNCONTROLLED BLOOD

PRESSUREPSEUDORESISTANCE poor BP technique poor adherence white coat effect under treatment

Apparent Resistant HTN

True Resistant HTN

• 30% non-adherent• 20% white-coat resistant• Overall, 50% with pseudo-

resistant HTN

• However, most were undertreated with none receiving chlorthalidone or spironolactone); only 40% receiving maximum dose of ACEi or ARB; and only 15% receiving maximum dose of CCB

JASH 2013

Hypertension 2013

Prevalence of Pseudo-Resistant Hypertension Secondary to Improper Blood Pressure Measurement Technique

Hemal Bhatt, Mohammad Siddiqui, Suzanne Oparil, David A. CalhounUniversity of Alabama at Birmingham

Objective: Compare normally obtained triage-BP measurement with expertly obtained BP measurement in patients referred for uncontrolled resistant HTN.

Results: 150 consecutive patients prescribed 3 or more antihypertensive agentsMean triage BP 148.8±23.1/83.7±14.4 mmHgMean expert BP 135.7±22.2/76.2±13.2 mmHg

21% of patients falsely diagnosed with uncontrolled resistant HTN2% of patients falsely diagnosed with controlled resistant HTN

Conclusion: Improper BP technique overestimates the prevalence of uncontrolled resistant HTN by 21%. Such a misdiagnosis may result in unnecessary diagnostic testing and/or medication titration in a large proportion of patients referred for resistant HTN.

Presented ASH Scientific Meeting 2015

0

20

40

60

80

100

120

BNP ANP

pg/m

l

HIGHALDOSTERONENORMALALDOSTERONECONTROLS

P=0.01

P=0.002

P<0.001

P=0.002

BNP and ANP Levels in Patients with High and Normal Aldosterone and Resistant Hypertension vs. Control Subjects

Gaddam et al., Arch Intern Med 2008

Potential Mechanisms of Excessive Fluid Retention in Patients with Resistant

Hypertension

• Hyperaldosteronism• Obesity• African American race• Chronic kidney disease• High dietary salt intake

SBP = systolic blood pressure; DBP = diastolic blood pressureNishizaka MK et al. Am J Hypertens 2003;16:925-930

BP Response to Spironolactone in PA and Non-PA Subjects

-25

-22

-18

-26-24-24

-30

-25

-20

-15

-10

-5

0

SBP

resp

onse

, mm

Hg

DB

P re

spon

se, m

m H

g

-15

-12

-8

-11

-9

-11

-30

-25

-20

-15

-10

-5

0

Primary AldosteronismNon-primary Aldosteronism

6 weeks 3 months 6 months 6 weeks 3 months 6 months

Chlorthalidone 25 mg vs. HCTZ 50 mg daily

Ernst et al. Hypertension. 2006;47:352

in

nig

httim

e B

P (m

m H

g)

P=0.009

P=0.288

After 8 weeks

SBP DBP

-7.2

-13.5

-4.6

-6.4

-16

-12

-8

-4

0

ChlorthalidoneHCTZ

Summary

• Prevalence of apparent resistant HTN of 15-20% of all treated hypertensive patients.

• Approximately 50% with true resistant HTN after excluding poor adherence and white coat effects. Of those, most undertreated with low use of chlorthalidone and spironolactone.

• Major risk factors include older age, CKD, African American race

• Etiology multifactorial but inappropriate fluid retention is seemingly an important mediator.

Resistant vs. Refractory HypertensionDifferent Phenoytpes?

Resistant Hypertension: requiring 4 or more antihypertensive medications, whether controlled or uncontrolled.

Refractory Hypertension: blood pressure that remains uncontrolled in spite of maximal medical therapy.

387 patients referred for RHTN

304 patients with adequate follow-up

275 patients with controlled RHTN

91.5%

29 patients with refractory hypertension

9.5%

83 excluded for inadequate follow-up

Results

Average f/u: 11 months

Average time to control: 3.5 months

Acelajado et al, J Clin Hypertens 2012

Baseline Demographic Characteristics

Parameter (Mean)

Refractory hypertension

(n=35)

Controlled RHTN

(n=140)P value

Age (years) 51.4 ± 12.8 55.4 ± 10.2 0.16

BMI (kg/m2) 33.2 ± 5.7 32.8 ± 5.9 0.75

SBP (mmHg) 174.6 ± 21.9 157.9 ± 24.6 0.025

DBP (mmHg) 97.0 ± 15.0 88.5 ± 15.2 0.005

Heart rate 76.1 ± 10.6 71.5 ± 10.8 0.03# African

Americans 16 (55%) 120 (44%) 0.23

# Females 16 (55%) 132 (48%) 0.46

# of BP drugs 4.9 ± 1.4 4.1 ± 1.0 0.004

BMI: Body mass index; SBP: Systolic blood pressure; DBP: Diastolic blood pressure.

Resistant vs. Refractory HypertensionDifferent Phenoytpes?

Resistant Hypertension: requiring 4 or more antihypertensive medications, whether controlled or uncontrolled.

Refractory Hypertension: blood pressure that remains uncontrolled in spite of maximal medical therapy.

Resistant vs. Refractory HypertensionDifferences in Mechanism?

• Resistant hypertension characterized by persistent fluid retention that is multifactorial in etiology.

• Hypothesis: Refractory hypertension or antihypertensive treatment failure is characterized by excess sympathetic output. 24-hr urinary excretion of normetanephrine clinic and ambulatory heart rate heart rate variability systemic vascular resistance (thoracic impedance)

• Alternative hypothesis: Refractory hypertension characterized by persistent fluid retention. Aldosterone levels, PRA, BNP Response to chlorthalidone/spironolactone Thoracic fluid content (thoracic impedance)

• Control group: controlled resistant hypertension

= 5% of patients referred for resistant HTNHypertension 2015

Response to SpironolactoneRefractory and Resistant Hypertensive Patients

Refractory Hypertension

•Definition: Uncontrolled hypertension on ≥ 5 different classes of agents, including chlorthalidone and spironolactone.•Prevalence of 3-10% of patients referred to a hypertension specialty clinic for resistant hypertension.•Risk factors include African American race and female gender.•Compared to controlled resistant HTN, not related to older age, obesity, CKD, higher sodium ingestion, or white-coat effects.•Evidence of heightened sympathetic tone to as suggested by greater greater clinic and ambulatory HR, greater urinary NE excretion, increased SVR, and reduced HR variability.•Seemingly not volume dependent as patients failing intensive diuretic therapy including spironolactone, no difference in aldosterone levels, BNP levels or thoracic impedance.

MSNA in Normotensives, Moderate and Severe Hypertension

Grassi et al., HYPERTENSION 1998

NEJM 2014

Explanation for Refractory Phenotype:Unique Mechanisms vs. Artifact

Artifact• Uncontrolled because non-adherent• Volume contraction (over-diuresed)• Vasodilator use• Underlying CHF• Controlled resistant adherent with beta antagonists

Unique Mechanisms• Obstructive sleep apnea• Genetics• Stress/anxiety/coping

\Acknowledgements

Maria C AcelajadoTanja DudenbostelEric JuddRoberto PisoniBin Zhang Eduardo PimentaSuzanne Oparil