resistant hypertension: management...

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Resistant Hypertension:Management Strategies

William C. Cushman, MDProfessor, Preventive Medicine, Medicine, Physiology

University of Tennessee Health Science Center

Chief, Preventive Medicine, Memphis VA Medical Center

Memphis, Tennessee

Miami Cardiac & Vascular Institute15th Annual Cardiovascular Disease Comprehensive

Symposium: From Prevention to InterventionNobu Eden Roc Hotel, Miami Beach, Florida

February 17, 2017

Presenter Disclosure Information

William C. Cushman, MD

“Resistant Hypertension: Management Strategies”

FINANCIAL DISCLOSURE:

Institutional Grants: Lilly

Uncompensated Consulting: Takeda

Calhoun et al. AHA Scientific Statement: Hypertension 2008;51:1403-1419

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© 2008, American Heart Association. All rights reserved.

• BP remaining above goal in spite of concurrent use of 3 antihypertensive agents of different classes.

• Ideally, 1 of the 3 agents should be a diuretic & all agents should be prescribed at optimal dose amounts.

• Resistant hypertension includes patients whose BP is controlled with use of >3 medications.

Resistant HypertensionDefinition

Calhoun et al. Hypertension. 2008;51:1403-19

AHA Scientific Statement

SBP Response to 2-Drug Combinations That Include or Do Not Include a DiureticSBP Response to 2-Drug Combinations That Include or Do Not Include a Diuretic

77

46

0

20

40

60

80

100

With HCTZ Without HCTZ

SBP <140 mm Hg, %

P=0.002

Materson, et al. J Human Hypertens 1995;9:791-796

Resistant HTN is thus defined in order to identify patients who are at high risk of having reversible causes of HTN and/or patients who, because of persistently high BP levels, may benefit from special diagnostic and therapeuticconsiderations

DefinitionRationale

AHA Scientific Statement Calhoun et al. Hypertension. 2008;51:1403-19

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Prevalence of Resistant Hypertension• True prevalence of resistant hypertension is not known1

• Depending on locale, studies estimate the prevalence around

– 10-30% in general practice– ≥ 50% in nephrology referral clinics2

• NHANES (2003-2008) estimated prevalence of resistant hypertension

– 8.9% (1 in 11) of US adults with hypertension– 12.8% (1 in 8) of all antihypertensive drug-treated US

adults with hypertension3

– More recent 2005-2008 estimates show the prevalence of resistant hypertension continues to increase4

1. Calhoun et al. Hypertension 2008;51:1403-14192. Kaplan NM. J Hypertens. 2005; 23:1441-1444. 3. Persell SD. Hypertension. 2011;57:1076-1080. 4. Egan et al. Circulation. 2011;124:1046-1058.

Muntner, Davis, Cushman, et al. Hypertension. 2014;64:1012-1021

Results were consistent across all major subgroups: age, sex, race, DM+/-, CHD+/-, CVD+/-

Treatment-Resistant Hypertension and the Incidence ofCVD and ESRD in ALLHAT

[Prevalence: 14%]

Cumulative Percent Controlled (BP < 140/90) at Five Years by Number of Drugs Prescribed

63

52

28

1

61

50

1

24

54

42

24

20

10

20

30

40

50

60

70

0 1 1 or 2 1, 2, or 3

Number of Prescribed Drugs

Per

cent

ALLHAT

ChlorthalidoneAmlodipineLisinopril

26%

49%

Cushman et al. J Clin Hypertens. 2008;10:751-760 .

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• High baseline BP• Older age• Obesity• Excessive dietary salt ingestion• Chronic kidney disease• Diabetes• Left ventricular hypertrophy• African American race• Female gender• Residence in southeastern United States

Patient Characteristics Associated With Resistant Hypertension



Lifestyle Factors Contributing to Resistant Hypertension

• Obesity or overweight

• High salt diet

• Physical inactivity

• Ingestion of low-fiber, high-fat diet

• Heavy alcohol ingestion


12 patients

6 patients low-salt diet

1 week

6 patients low-salt diet

1 week

6 patients high-salt diet

1 week

6 patients high-salt diet

1 week

wash-out2 weeks

Resistant Hypertension: High/Low Dietary Salt Cross-Over Evaluation

Low Na

50 mmol/d

High Na

250 mmol/d

3.4 BP meds

Office BP =

146/84 mm Hg

3-6 gram

Na+ diet High Na

250 mmol/d

Low Na

50 mmol/d

Pimenta, E et al. Hypertension 54: 475-481, 2009

Seated Blood Pressure/ ABPM

24-hr Urine for Na, K, Aldo

BNP, PRA

PWV, AIx

5

Large Reduction in Systolic and Diastolic

24h BP with Dietary Na Restriction

24

h a

mb

ula

tory

BP

Pimenta, E et al. Hypertension 54: 475-481, 2009


Causes of Resistance to Hypertension Treatment

• Poor adherence with prescribed medications

• Inaccurate BP measurement

• White coat hypertension


Overestimation of BP in VA:Routine Clinic BPs (CPRS) vs Random Zero Mercury

Manometers (Standard Technique with Trained Observe rs)

8.3

7.1

0

2

4

6

8

10

Systolic Diastolic

BP

Dif

fere

nc

e,

mm

Hg

: C

PR

S-R

Z

Kim JW, et al. J Gen Intern Med. 2005;20:647-9

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BP Measurement:Of Paramount Importance!

� Patient seated with back supported and arm bared an d supported at heart level.

� Patient should refrain from smoking or ingesting ca ffeine for 30 minutes prior to measurement.

� Measurements should begin ≥5 minutes of rest (patient should not talk and not be spoken to).

� Use appropriate cuff size and validated equipment .� If manual determination:

� Determine pulse obliteration pressure (POP) for SBP estimate: then inflate to about 30 mm Hg above POP.

� Rate of ““““column ”””” drop: 2 mm Hg/second or beat initially.� Both SBP and DBP should be recorded.� >2 readings: averaged or use median of 3 readings.


• Non-Narcotic Analgesics - Non-steroidal anti-inflammatory agents including a spirin- Selective COX-2 inhibitors

• Sympathomimetic agents- decongestants- diet pills- cocaine

• Stimulants -methylphenidate-dexmethylphenidate,-dextroamphetamine- amphetamine, methamphetamine-modafinil

Substances that Can Interfere with Blood Pressure Control



Substances that Can Interfere with Blood Pressure Control

• Alcohol

• Oral contraceptives

• Cyclosporine

• Erythropoietin

• Natural licorice

• Herbal compounds- ephedra - ma huang


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Common

• Obstructive sleep apnea

• Renal parenchymal disease

• Primary aldosteronism

• Renal artery stenosis

Secondary Causes of Resistant Hypertension



Secondary Causes of Resistant Hypertension

Uncommon

• Pheochromocytoma

• Cushing ’’’’s disease

• Hyperparathyroidism

• Aortic coarctation

• Intracranial tumor


Original Article

Stenting and Medical Therapy for Atherosclerotic Renal-Artery Stenosis

Christopher J. Cooper, M.D., Timothy P. Murphy, M.D., Donald E. Cutlip, M.D., Kenneth Jamerson, M.D., William Henrich, M.D., Diane M. Reid, M.D.,

David J. Cohen, M.D., Alan H. Matsumoto, M.D., Michael Steffes, M.D., Michael R. Jaff, D.O., Martin R. Prince, M.D., Ph.D., Eldrin F. Lewis, M.D.,

Katherine R. Tuttle, M.D., Joseph I. Shapiro, M.D., M.P.H., John H. Rundback, M.D., Joseph M. Massaro, Ph.D., Ralph B. D'Agostino, Sr., Ph.D.,

Lance D. Dworkin, M.D., for the CORAL Investigators

N Engl J MedVolume 370(1):13-22

January 2, 2014

The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study

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CORAL: Kaplan–Meier Curves for the Primary Outcome

Cooper CJ et al. N Engl J Med 2014;370:13-22

N=947

Adv

erse

CV

and

rena

l eve

nts

SBP 2.3 mm Hg lower in stent group; P = 0.03

Initial Choices of MedicationsInitial Choices of Medications

Diuretics

ACE inhibitorsor

ARBs*

Calciumantagonists

* Recommended for CKDCombining ACEI with ARB discouraged

ββββ-blockers should be included in the regimen if ther e is a compelling indication for a ββββ-blocker

Diuretics or CCBs in Blacks

Chlorthalidone 25 mg Vs. HCTZ 50 mg:

Change in 24-Hour Mean Systolic Blood Pressure

Ernst ME, et al. Hypertension. 2006;47(3):352-358.

-15

-10

-5

0

24-Hour Mean Daytime Mean Nighttime Mean

HCTZ 50 mg/d, n=16

Chlorthalidone

25 mg/d, n=14

P=0.230

P=0.009

P=0.054

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Treatment of Resistant Hypertension

• Consider addition of mineralocorticoid receptor antagonist [or amiloride]

• Use of loop diuretic may be necessary in patients with [stage 4] CKD (eGFR <30 mL/min)


Prevalence of Primary Aldosteronism in Subjects With Resistant Hypertension

19%

22%20%

17%

0

5

10

15

20

25

Seattle Birmingham Oslo Prague

1. Gallay BJ, et al. Am J Kidney Dis. 2001;37:699-705. 2. Calhoun DA, et al. Hypertension. 2002;40:892-896. 3. Eide IK, et al. J Hypertens. 2004;22:2217-2226. 4. Strauch B, et al. J Hum Hypertens. 2003;17:349-352.

Pre

vale

nce

of P

A,

%

PA = Primary aldosteronism.

1 2 3 4

PATHWAY-2 Study DesignThe Prevention And Treatment of Hypertension With Algorithm

based therapY (PATHWAY)

Spironolactone

25 – 50mg o.d.

Doxazosin MR

4 – 8mg o.d.

Bisoprolol

5 – 10mg o.d.

Placebo

Screening for

Resistant Hypertension

• Rx A + C + D

• DOT* to exclude non-

compliance

• Home BP to exclude

white coat hypertension

• Secondary hypertension

excluded

4 week

Single blind placebo run in

Treated with A+C+D

Randomisation

*DOT = Directly Observed Therapy

Double blind, Randomised, Placebo-Controlled, Cross-over Study

• 12 weeks per treatment cycle

• Forced titration; lower to higher dose at 6 weeks

• No washout period between cycles

Home Systolic BP

measured at

6 and 12 weeks

Williams B, et al. BMJ Open, 2015

Amiloride

Open-Label

Run-out

10 -20mg o.d.

Plasma

Renin

10

The Prevention And Treatment of Hypertension With Algorithm

based therapY (PATHWAY) 2: Primary Outcome

(Average Home SBP) XXXXXXX

76

78

80

82

84

86

134

136

138

140

142

144

146

148

150

B P S D B 11Baseline Placebo Spironolactone

p<0.001

Doxazosin Bisoprolol

p<0.001

Hom

e B

P (

mm

Hg)

Dia

sto

lic

Systo

lic

Williams, et al. Lancet, published online September 21, 2015

2X2 factorial design (n=98): amiloride (10 mg/d)spironolactone (25 mg/d)combination of both drugsplacebo

Saha, et al. Hypertension. 2005;46:481-487

Improvement in BP in Blacks Uncontrolled with Diuretic+CCB

Diuretics

ACE inhibitorsor

ARBs

Calciumantagonists

* Compelling indications may modify this.

Can add: mineralocorticoid antagonist or amiloride, αααα-blocker, alternative CCB, vasodilator,

ββββ-blocker, αβαβαβαβ-blocker, and/or central agonist

Combinations of Medications*Combinations of Medications*

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• If a specific secondary cause of HTN is suspected in a patient with resistant HTN, referral to the appropriate specialist is recommended as needed.

• In the absence of suspected secondary causes of HTN, referral to a HTN specialist is recommended if the BP remains elevated in spite of 6 months of treatment. [Note: I would not recommend waiting 6 months, but refer whenever BP is not controlled and provider is unsur e what to do next – this is what most do in VA because of B P performance measure]

Referral to a Specialist


Bhatt DL, et al. N Engl J Med 2014;370: 1393-1401

Primary Efficacy Outcome:

Office SBP at 6 months

Bhatt DL, et al. NEJM

2014;370: 1393-1401

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Device- Based Therapy for Resistant Hypertension: Not Ready for Prime Time

�Baroreflex ActivationTherapy- still being investigated

�Renal Denervation Therapy- re-designed the trials which are ongoing

We will have to wait to see if either of these devices meet with future FDA approval

Not FDA Approved

Summary/Take Home Messages

• Resistant HTN is a common clinical problem, and is a marker of increased CVD risk

• Common factors related to resistant HTN include older age, obesity, DM, CKD, high salt diet, African American race, inconsistent adherence, and living in the southeastern U.S.

• Patients with resistant HTN may benefit from further evaluation, intensification of antihypertensive lifestyle and drug regimen, and/or referral to a hypertension specialist.

• Intensify regimen by combining agents from 3 major classes (diuretic, RAS blocker, CCB) at effective doses, with effective use of thiazide-type diuretics such as chlorthalidone, then, if necessary, add spironolactone or amiloride and/or a vasodilator.

Questions?

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