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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