treating resistant hypertension
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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
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
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