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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
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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
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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
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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
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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
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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
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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%
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Once true RH has been confirmed, identify and treat contributing and
secondary causes
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Carey RM et al Hypertension 2018
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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
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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
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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%
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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]
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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
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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
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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.
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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
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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
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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