Resistant hypertension

RESISTANT HYPERTENSION
Recognition and Management
Prem Mohan Jha
DNB Nephro SR
Max Super Speciality Hospital, Vaishali
11/28/2020 1

Introduction
• Hypertension is the world’s leading risk factor for CVD, stroke,
disability, and death.
• A large proportion of hypertensive adults, still fail to achieve
their recommended BP treatment targets.
• These individuals remain at increased risk for target organ
damage, morbidity, and mortality despite ongoing
antihypertensive drug therapy.
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Definition of rHTN
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www.thelancet.com Vol 386 October 17, 2015
Blood pressure that remains above goal in spite of the
concurrent use of 3 anti hypertensive agents of different
classes.
•Ideally, one of the 3 agents should be a diuretic.
•Prescribed at optimal dose amounts.
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www.thelancet.com Vol 386 October 17, 2015
Without CKD : 0.5 – 14.3%
With CKD : 1.6 – 24.7%
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Why Hypertension Is Important
• High BP causes :
-50% of all stroke deaths
-50% of all congestive heart failure
-35% of all cardiovascular deaths
-25% of all premature deaths.
Prevalence and prognostic significance of apparent treatment resistant hypertension in chronic kidney
disease: Report from the Chronic Renal Insufficiency Cohort Study. Hypertension 67: 387–396, 2016
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High Risk Patients
1. Older age
2. Obesity
3. Black
4. Female
5. Southeast united states
6. DM
7. CKD
8. High salt intake
9. High baseline BP
10. LVH
https://www.ahajournals.org/journal/hyp
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Causes
Apparent Cause
o Poor adherence
o Improper techniques of BP
measurement
o White coat effect
o Treatment inertia
True Resistant Hypertension
o Life style Factors
 Obesity
 Alcohol
 Inactivity
 Dietary pattern
o Drug related
o Sleep Apnoea
o Secondary causes
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Nonadherence
• There is no gold standard for measuring adherence.
• Indirect methods such as pill count, self-report, and
prescription refill Data.
– Simple, inexpensive, and widely used.
– However, they can easily be manipulated to overestimate adherence.
• Direct methods such as urine or blood measurement of drug
or metabolites is considered more robust but is relatively
expensive, is of limited availability, and does not perfectly
reflect level of adherence.
• All methods have limitations, and ideally, accurate assessment
of adherence should involve a combination of approaches.
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Poor BP Measurement Technique
• Emptying a full urinary bladder
• Sitting with legs uncrossed
• Back, arm, and feet supported in a quiet room
• Seated atleast 5 minutes before the first reading.
• Choosing a BP cuff with a proper size bladder
• Obtaining a minimum of 2 readings 1 minute apart
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White-Coat Effect
• The white-coat effect is the observation of repeated BP
elevations in the office with controlled or significantly lower
BP outside the office.
• A clinically significant white-coat effect may be present in 28%
to 39% of individuals with rHTN by office BP measurement.
• The white-coat effect can be easily identified by 24-hour
ABPM.
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Lifestyle Factors
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Obesity
• Recent findings from the NHANES of 13 375 hypertensive
adults demonstrate that body mass index (BMI) ≥30 kg/m2
approximately doubles the risk for rHTN.
• Spanish Ambulatory Blood Pressure Monitoring Registry.
• Kaiser Permanente Southern California health system.
– Confirmed the same findings.
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Obesity
Obese
Pt
OSA
Inflammation/
oxidative stress
SNS
activation
Na/ volume
retentionInsulin + leptin resistance
Renal
dysfunction
Other drugs causing
hypertension
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Endothelial
dysfunction

Obstructive Sleep Apnea
• Untreated OSA is strongly associated with hypertension and
in normotensive persons predicts development of
hypertension
• Sleep apnea is particularly common in patients with resistant
hypertension.
• In an observational study evaluation of 41 consecutive patients
with treatment-resistant hypertension, 83% were diagnosed
with unsuspected sleep apnea based on an apnea hypopnea
index 10 events/h.
• Obstructive sleep apnea is observed in 30% to 40% of patients
with hypertension and in 60% to 70% of patients with resistant
hypertension.
Circulation June 24, 2008
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Dietary Sodium
 Excess volume retention,
 Vascular dysfunction,
 Arterial stiffness,
 Sympathetic activation,
 Impaired reninangiotensin axis suppression,
 Mineralocorticoid receptor activation,
 Immune cell modulation.
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Alcohol
• The dose-response association may differ between men
(linear) and women (J shaped)164 and can be modified by
metabolic genes.
• Nonetheless, heavy alcohol intake (>30–50 g/d) is a well-
established risk factor for hypertension.
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Dietary Pattern and Other Risk Factors
• The Dietary Approaches to Stop Hypertension (DASH) eating
pattern is well established to reduce BP, by 6.7/3.5 mm Hg in a
recent meta-analysis.
• Psychosocial stressors (eg, occupational stress, low social
support), negative personality traits (anxiety, anger,
depression), and reduced sleep duration/ quality have also
been associated with high BP.
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Drug-Related RH
• NSAIDs
• Oral contraceptives
• Sympathomimetic
• Cyclosporine, tacrolimus
• Erythropoietin
• VEGF inhibitors
• Cocaine
• Amphetamines
• Antidepressants
• Glucocorticoids, mineralocorticoids
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Secondary Hypertension: Causes
 Primary Aldosteronism
 Renal Parenchymal Disease
 Renal Artery Stenosis
 Pheochromocytoma/Paraganglioma
 Cushing Syndrome
 Coarctation of the Aorta
 Other Causes of Secondary Hypertension
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Evaluation Of Resistant
Hypertension
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Management Of Resistant
Hypertension
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Lifestyle Modification
• Weight Loss
• Dietary Salt Restriction
• DASH Diet
• Exercise
• Alternative Approaches
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A diet rich in fruits, vegetables, and low-fat dairy foods and
with reduced saturated an total fat can substantially lower
blood pressure.
This diet offers an additional nutritional approach to
preventing and treating hypertension.

Indications, Contraindications, And
Adverse Effects For Diuretics
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American Journal of Hypertension 29(10) October 2016

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American Journal of Hypertension 29(10) October 2016

Hypertension. 2011;57:1069-1075
The APBM nighttime systolic, 24-hour ABPM systolic, and office systolic BP
values were significantly decreased by spironolactone (difference of 8.6, 9.8,
and 6.5 mm Hg; P0.011, 0.004, and 0.011), whereas the fall of the respective
diastolic BP values was not significant (3.0, 1.0, and 2.5 mm Hg; P0.079, 0.405,
and 0.079). The adverse events in both groups were comparable.
In conclusion, spironolactone is an effective drug for lowering systolic BP in
patients with resistant arterial hypertension.
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Lancet 2015; 386: 2059–68

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Spironolactone was the most effective add-on drug for the treatment of
resistant hypertension.

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J Clin Hypertens (Greenwich). 2016;18:1162–1167.
Minoxidil treatment was associated with a significant reduction
in blood pressure from 162/83 mm Hg to 135/ 72 mm Hg
(P<.0001).

Minoxidil
• Dosing Considerations
– The beginning dose of minoxidil can be as low as 2.5 mg/d
with a maintenance dose generally falling in the range of
10–40 mg/d.
– Minoxidil can be given from once to three times daily with
the most common frequency of administration being twice
daily.
– Although the manufacturer’s maximum recommended
dose is 100.
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Primary Aldosteronism
• The disorder includes hypertension caused by volume expansion
and sympathetic nervous system activation, hypokalemia,
metabolic alkalosis, and advanced cardiovascular and renal
disease.
• Stroke (4.2-fold), myocardial infarction (6.5-fold), and atrial
fibrillation (12.1-fold).
• Others : left ventricular hypertrophy, diastolic dysfunction and heart
failure, large artery stiffness, oxidative stress, widespread tissue
inflammation and fibrosis, and increased resistance vessel
remodeling compared with primary hypertension.
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• Prevalence of primary aldosteronism
– ≈8% overall in primary hypertension.
– ≈20% in patients with confirmed rHTN.
• All resistant hypertension patients should be
screened.
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• Two types of renin assays are in routine clinical use.
– One measures renin activity,
– second measures the amount of immunoreactive renin.
– For the plasma renin activity, the normal range is 1.9 to 3.7 ng Ang
I/ml/h, and the lower level of detectability is 0.1 ng Ang I/ml/h.
– For the direct renin assay, the normal range is typically 13 to 44
IU/ml and lower level of detectability is 6 to 8 IU/ml.
• Therefore the typical ARR, for a patient with primary hypertension not
receiving drugs that alter the renin-angiotensin system, is about 10 : 1
when using the plasma renin activity and 1 : 1 with the direct renin
assay.
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Aldosterone-Renin Ratio (ARR)

• Spironolactone,
• Eplerenone,
• Amiloride
• β-adrenergic receptor blockers,
• Central α2-receptor agonists,
• Renin inhibitors
• ACE inhibitors,
• ARBs,
• Non–potassium-sparing diuretics,
• Dihydropyridine CCBs
Should be withdrawn 1 month before test
Should be withdrawn 2
weeks before test
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11/28/2020 44
The Journal of Clinical Endocrinology & Metabolism, Volume 93, Issue 9, 1 September 2008,
Pages 3266–3281

• Adrenal Vein Sampling
– For determining whether autonomous aldosterone
release is due to unilateral or bilateral disease.
– SELECTIVITY INDEX- The ratio of adrenal vein to
inferior vena cava cortisol concentration, should be
determined and should be at least 5 : 1 for each
adrenal vein sample to confirm successful adrenal vein
cannulation.
– LATERALIZATION INDEX- The ratio of adrenal vein
aldosterone to adrenal vein cortisol.
– Calculated by dividing the greater adrenal vein ratio
by the lesser adrenal vein ratio.
– A lateralization index greater than 2.0 supports a
diagnosis of an APA.
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Treatment
• Surgical
– Adrenalectomy
• Medical
– Mineralocorticoid Receptor Antagonists.
– Non–Mineralocorticoid Receptor Blocker Therapy
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• Oral SPIRONOLACTONE 25 to 50 mg/day.
• Dose titration on a 2- to 4-week basis.
– Most patients can be treated with maximum dose of 100 mg/day, but
occasional patients may require 200 to 400 mg/day, often administered
twice a day.
• EPLERENONE can be used at similar doses and with a similar dose escalation
pattern, with the that the general maximum recommended dose is only 100
mg/day.
• FINERENONE is a novel, selective, nonsteroidal MR blocker that may have less
effect on serum potassium.
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• Non–Mineralocorticoid Receptor Blocker Therapy
– ENaC Inhibitors
• Amiloride
• Triamterene
– Aldosterone Synthase Inhibitors
• Developmental
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Renal Artery Stenosis
• Hypertension accelerated or worsened by renal artery stenosis
remains among the most common causes of RH, particularly in
older age groups.
• More recent series indicate that 24% of older subjects (mean age,
71 years) with RH have significant renal arterial disease.
• Most patients with renovascular disease tolerate ACE inhibitor or
ARB therapy without adverse renal effects, but a modest fraction
(10%–20%) will develop an unacceptable rise in serum creatinine,
particularly with volume depletion.
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• A subset of medically treated patients develop progressive
disease syndromes with worsening hypertension, renal
insufficiency, or circulatory congestion (“flash pulmonary
edema”), which carry high mortality risks.
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• Restenosis may develop in 15% to 24% of treated patients but
may not always be associated with worsening hypertension or
kidney function.
• Duplex imaging to identify increased peak systolic velocity in
the renal arteries is most commonly used, often with
confirmation by computed tomography angiography or
magnetic resonance angiography before invasive studies.
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USE OF DOPPLER ULTRASONOGRAPHY TO PREDICT THE
OUTCOME OF THERAPY FOR RENAL-ARTERY STENOSIS
N Engl J Med, Vol. 344, No. 6 February 8, 2001
A renal resistance-index value of at least 80 reliably identifies
patients with renal-artery stenosis in whom angioplasty or
surgery will not improve renal function, blood pressure, or kidney
survival.
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Substantial risks but no evidence of a worthwhile clinical benefit from
Revascularization in patients with atherosclerotic renovascular
disease.
N Engl J Med 2009;361:1953-62.
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ASTRAL TRIAL

Renal-artery stenting did not confer a significant benefit with respect to the
prevention of clinical events when added to comprehensive, multifactorial medical
therapy in people with atherosclerotic renal-artery stenosis and hypertension or
chronic kidney disease.
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CORAL TRIAL

Pheochromocytoma/Paraganglioma
• The chromaffin cell tumors, pheochromocytoma (adrenal
catecholamine producing, 90%) and paraganglioma (extra-
adrenal, sympathetic/parasympathetic derived, 10%), are rare
even in the hypertensive population, with a prevalence
estimated at 0.01% to 0.2%.
• The prevalence is likely higher in patients referred for RH (eg,
up to 4%).
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• Symptoms :
– Paroxysmal hypertension
• Sustained in up to 50% of those with high norepinephrine production
• Orthostatic in epinephrine-predominant tumors
– Headache, palpitations, pallor, and piloerection (“cold
sweat”).
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• The screening test of choice:
– Measurement of circulating catecholamine metabolites.
– Catechol O-methyl transferase releases normetanephrine and
metanephrine from the tumors, measured as plasma free (sensitivity,
96%–100%; specificity, 89%–98%) or urinary fractionated (sensitivity,
86%–97%; specificity, 86%–95%) metanephrines.
• The levels are usually <4 times the upper limit of normal.
• If still elevated, they can be further evaluated as false positives by
clonidine-suppression testing, with 100% specificity and 96% sensitivity of
failure to reduce plasma metanephrines by 40%.
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The Oncologist 2008;13:000 – 000

Coarctation of the Aorta
• Patients with operated coarctation of the aorta are likely to have
hypertension in adulthood and are at risk for premature CVD,
including myocardial infarction, aortic aneurysm, stroke, and heart
failure.
• Because persistent hypertension may be secondary to increased
sympathetic tone, β-blockers may be most useful for BP control.
• Antihypertensive therapy typically also includes an ACE inhibitor or
an ARB.
• If hypertension is resistant to treatment, surgical or catheterbased
intervention.
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Novel Therapies
 Renal dinnervation
 Baroreceptor Activation Therapy
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Negative Trialn engl j med 370;15 nejm.org april 10, 2014
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Substantial BP reduction without any major safety signals11/28/2020 64

The weight of the overall evidence suggests that over the long-term, BAT can safely
reduce SBP in patients with resistant hypertension.
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Resistant hypertension

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