Treating Resistant Hypertension: Pearls and Updates

Erika R. Drury, MD

Assistant Professor of Medicine

Division of Nephrology

University of Rochester School of Medicine

Assistant Director University of Rochester AHA Comprehensive Hypertension Center

Conflicts of Interest

I have no disclosures

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Objectives1. Accurately diagnose resistant hypertension [exclude pseudo-resistant

hypertension]

2. Perform a secondary hypertension workup [in the appropriate patient

at the appropriate time]

3. Utilize key lifestyle and medication strategies to treat resistant hypertension

Focus on recent pearls and updates for the practicing clinician

Resistant Hypertension (RH) is highly prevalent and associated with increased CVD risk

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More likely to have a secondary cause of hypertension

More likely to have medication adverse effects

Higher risk of CVD

morbidity and mortality

Carey RM et al Hypertension 2018

Resistant Hypertension (RH)

Blood pressure elevated above goal •Despite the use of 3 anti-hypertensive drug classes

•Long-acting calcium channel blocker•Renin-angiotensin system blocker•Diuretic

*Maximum or maximally-tolerated doses

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Apparent treatment-resistant hypertension (aTRH)

True RH

Pseudo-resistant hypertension

Inaccurate BP measurementWhite-coat effectMedication non-adherenceUnder-treatment

Medication non-adherence is common in aTRH

Using DOT, 50% of patients with

apparent RH were non-adherent to therapy

Mean drop in 24-hr ABP of 19/9 mmHg after DOT

Hameed MA et al J Hum Hypertens 20167

Medication non-adherence is common in aTRH

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Using urine toxicological analysis,

53% of patients with apparent RH

were non-adherent

Majority were taking < 50% of

prescribed drugs

30% were taking no drugs

Jung O et al J Hypertens 2013

Identifying and Correcting Non-adherence• Direct assessment and questioning

• “When taking multiple medications, it is common to miss doses. How many times do you miss taking your BP medications in a week?”

• Validated scales• MMAS-8 Morisky medication Adherence Scale

• Pill count• Prescription refill data• Direct measurement of urine or blood drug metabolites by LC-MS• Effective strategies in the general HTN population that can be extrapolated to the

RH population:• Use of medications that are dosed daily• Combination agents• 90- versus 30- day prescriptions to consolidate refills

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A common cause of pseudo-resistant hypertension is under-treatment

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Carey RM et al Hypertension 2018Ɨ Egan BM et al Hypertension 2013, Bhatt H et al J Am Soc Hypertens 2016

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Hypertension 2013

147,635 uncontrolled hypertensives

44,684 ≥ 3 anti-HTN

22,189 optimal therapy

Only half of patients with aTRHwere prescribed optimal therapy

30%

15%

Once true RH has been confirmed, identify and treat contributing and

secondary causes

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Carey RM et al Hypertension 2018

Evaluation for Secondary Hypertension

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Adapted from WheltonPK et al Hypertension 2017

Cause [in the context of RH]

Clinical Features[not exhaustive]

Screening Tests

Renovascular disease • Atherosclerosis, vascular disease

• Recurrent flash pulmonary edema

• Renal duplex doppler US• MRA• Abdominal CT

Obstructive sleep apnea • Obesity• Snoring• Daytime sleepiness• Non-dipping

• Polysomnography

Primary aldosteronism • May have none• Hypokalemia• OSA• Atrial fibrillation

• ARR*

Pheochromocytoma, paraganglioma

• Paroxysmal hypertension• Labile BP • Headache, palpitations,

sweating

• 24-h urinary fractionated metanephrines

OSA in Resistant Hypertension

Prevalence of OSA in RH from prospective analyses of 55-83% (Gonzagga

CC et al Clin Sleep Med 2010, Logan AG et al J Hypertens 2001, Muxfeldt ES et al Am J Hypetens 2014)

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Pedrosa RP et al Hypertension 2011

OSA was identified in 64% of patients with RH

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Martinez-Garcia MA JAMA 2013

Primary Aldosteronism

Generally underrecognized

Biochemically-overt PA can be seen across the entire spectrum of hypertensive disorders

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Adjusted prevalence of renin-independent aldosterone secretion among RH cohort was 51.6%

Screening for PA in RH

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All patients with RH should be screened. Current screening rates in RH are around 2%.

• - Most widely accepted – ARR >/= 30 ng/dL per ng/ml/hr [morning, seated] in the context of a suppressed renin and an aldosterone concentration > 15 ng/dL

• - Brown JM et al – Among RH, 24.5% of confirmed cases had serum aldosterone < 10 ng/dL

* Stop MRAs, don’t worry about other drugs initially

* If a random PRA is suppressed < 1 ng/mL/hour, strongly suggestive of PA

* Most patients can sodium load with diet for confirmatory testing [24 hour urine aldosterone excretion > 12 mcg AND urine sodium excretion > 200 mEq]

Maximize lifestyle and diet

• Dietary sodium restriction • Limiting dietary sodium to 50 mmol/d (1,150 mg/d) decreased office BP by 22.7/9.2

mmHg in patients with RH • Limiting dietary sodium to 75 mmol/d (1,725 mg/d) decreased BP by 9.7/3.9 mmHg

in patients with Stage 3/4 CKD

• 24-hour urine sodium excretion can be used to evaluate daily sodium intake and guide dietary advice

• DASH diet has not been studied specifically in RH20

Pimenta E et al Hypertension 2009McMahon EJ et al J Am Soc Nephro 2013

Medications (and devices) in the management of RH

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Hypertension 2018

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Volume excess

Aldosteronism

Increased sympathetic tone

Diuretics

Mineralocorticoid receptor antagonists

Sleep disorders, anxiety, obesity, beta blockers

Diuretics• Thiazide-like diuretics: chlorthalidone (12.5-25 mg) or indapamide

(1.25-2.5 mg)• Greater potency

• Longer half lives (improved nighttime BP control?)• Meta analysis of 21 studies – reduction in CV events and heart failure was

significant for thiazide-like diuretics irrespective of the adjustment for blood pressure (Olde Engberink RH et al. Hypertension 2015)

• Loop diuretics added to or in place of thiazide-like diuretic when GFR<25-30 ml/min• Once daily torsemide or twice daily furosemide• Titrate to an effective “dry weight”

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Burnier M et al. J of Hypertens. 2019. DiNicolantonio JJ et al. Future Cardiol. 2015.Fay KS and Cohen DL. Am J Kidney Dis. 2021.

Mineralocorticoid receptor antagonists• Spironolactone (12.5 – 50mg daily) or eplerenone (25 – 50mg BID)

• Even in patients without clear primary aldosteronism, MRA are the best 4th

drug for RH

• PATHWAY-2 and AMBER trials

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Lancet 2015

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Lancet 2015

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Lancet 2019

Time to spironolactone discontinuation

At week 12, 66% in the placebo group and 86% in the patiromer group remained on spironolactone (p<0.0001)

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Time to serum potassium >/= 5.5 mmol/L

Cumulative dose of spironolactone was higher with patiromer than with placebo

No significant difference in automated office blood pressure from baseline to week 12 between treatment groups

Lancet 2019

Additional add-on therapy

• Beta blockers – prefer combination alpha/beta blockers [labetalol, carvedilol]

• Central Alpha antagonists – clonidine [patch] or guanfacine [at bedtime]

• Hydralazine or minoxidil – require use of a beta blocker and diuretic to

counteract reflex tachycardia and fluid retention, respectively

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Device-based treatment

- Renal denervation

- Carotid baroreflex activation therapy

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NEJM 2014Lancet 2015

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Sustained reduction in 24-hour ABPM

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Systolic(Baseline: 176 mmHg)

Diastolic(Baseline: 107 mmHg)

Heart Rate(Baseline: 80 bpm)

Cha

nge

in m

mH

g or

BPM

*All p values < 0.005^All p values <0.05

Scheffers et al J Am Coll Cardiol 2010

Clinical Pearlso Exclude pseudo-resistant hypertension, especially medication non-adherence

o Don’t discount the power of lifestyle changes

o OSA and [primary] aldosteronism are common contributing/secondary causes in RH

o Use a thiazide-like diuretic

o Add [or substitute] loop diuretics in advanced CKD

o Spironolactone regardless of plasma renin activity

o Promise of device-based treatments? 35