RESISTANT

HYPERTENSION

Chair person – Dr Prashanth V N (Professor & HOU)

Co chairperson – Dr Chandrashekar M (Assistant Prof)
Presenter – Dr Suraj chavan
CONTENTS
 [Link] OF HYPERTENSION

 [Link] DEFINITION

 [Link] 2018 VS JNC -8

 [Link] HYPERTENSION DEFINITION

 [Link] →WHITE COAT HYPERTENSION

 [Link] , PROGNOSIS

 [Link] CHARACTERISTICS

 [Link] OF RH INCLUDING SECONDARY HYPERTENSION

CONTENTS CONT..
 [Link] OF RH

 [Link] OF RH

 11. DEVICE BASED MANAGEMENT OF RH

HISTORY
 History – Estimation
of BP originated in
1733
 Sir Stephen Hales
Introduced a Brass
pipe connected to a
glass tube into a
horse’s leg artery
 Observed the rise of
the Blood column to
8 ft 3inchabove the
level of left
ventricles.
HYPERTENSION
 Hypertension -Progressive cardiovascular
syndrome characterised by the presence of
blood pressure elevation to a level at which
the institution of therapy reduces blood
pressure-related morbidity and mortality

 Office BP of 140/90 or higher (ESH 2018)

 Various guidelines define normal blood

pressure differently.
 Blood pressure: Force exerted by the
blood against unit area of the vessel wall

 Pulse Pressure: SBP-DBP

 Mean arterial pressure :Arterial
pressures measured by over a period
of time: (1/3 SBP + 2/3 DBP) or (DBP
+1/3 PP) Normal MAP: 70-110 mmHg
Perfusion to vital organs.
JNC 8 CLASSIFICATION OF BP IN ADULTS
>18YR

CLASSIFICATI SBP (MMHG) DBP(MMHG)

ON
NORMAL <120 AND <80
PREHYPERTENSI 120-139 OR 80-89
ON
STAGE 1 HTN 140-159 OR 90-99
STAGE 2 HTN >160 OR >100
COMPARISON OF AHA (2018) WITH JNC 8

AHA (2018) JNC -8

 Based on SPRINT trial  Based on ACCORD trial
Published in 2015 after JNC 8  Focussed on Higher BP since (Failed to
show statistically significant mortality
 Focussed on stricter treatment and morbidy benifit in Diabetes with
stricter blood pressure )
threshold ,lower target BP goals
 Threshold for Rx
 Threshold for Rx Age>60yr:150/90
>130/80 if H/o CVD age <60yr or comorbid
OR condition :140/90
>10% ASCVD Risk
 Treatment goals
<140/90 if <60yr or comorbid cond
 Treatment goals
<150/90 if >60yr
<130/80 mmhg
 Treatment algorithm:
 Treatment algorithm: 1Rx for stage 1
Start 1 Rx→ follow up 1mo→add Rx 2 Rx for stage 2 with diff MOA
or increase dose
 Pitfalls –
on data prior to 2013 ,limited
 Pittfalls -New def- increases the
data over long term sequelae
 RESISTANT HYPERTENSION(RH) :-
Definition

 RH is defined as the BP of a hypertensive

patient ≥3 antihypertensive agents of
different classes, commonly including a
long-acting (CCB), a blocker of the renin-
angiotensin system ( [ACE] or [ARB]),
and a diuretic at a maximal dose. (AHA
2018)
 RH also includes patients whose BP
achieves target values on ≥4
antihypertensive.

The term RH refers to hypertension with

both uncontrolled and controlled BP,
depending on the number of
antihypertensive agents used.
Ideal measurement of Resistant
hypertension
 1) BP should be measured and the BP threshold for diagnosis
and treatment goals should be in accord with current clinical
practice guidelines ; >130/80( AHA GUIDELINES )

 (2) Patients should be taking ≥3 antihypertensive agents,

commonly including a long-acting CCB, a blocker of the renin-
angiotensin system (ACE inhibitor or ARB), and a diuretic at
maximum or maximally tolerated doses;

 (3) Patients with the white-coat effect should not be included

in the definition of RH; and

 (4) The diagnosis of RH requires the exclusion of

antihypertensive medication nonadherence.
PSEUDORESISTANCE
 White coat hypertension
 The “white-coat effect” is defined as office
BP above goal but out-of-office BP below goal
in a patient on ≥3 antihypertensive agents.
(AHA )
 Diagnosed by –ABPM
PREVALENCE
 The term apparent treatment RH (aTRH)
is used when ≥1 are missing:
 medication dose,
 adherence,
 out-of-office BP;
 Among treated adults with hypertension,
prevalent aTRH occurs
 ≈12% to 15% of population-based.
 15% to 18% of clinic-based reports.
PROGNOSIS
 RH is associated with higher risk of
myocardial infarction, stroke, peripheral
arterial disease, heart failure, and all-cause
mortality as compared with patients without
RH.

 Conversely, RH is not associated with

increased adverse clinical events in patients
with HFrEF and may lower the risk for heart
failure–related rehospitalization.(AHA)
PATIENT CHARACTERISTICS
 Very high proportions (60%–84%) of
individuals with RH have sleep apnea
 Obesity,
 left ventricular hypertrophy,
 METABOLIC DERANGEMENT-diabetes
mellitus, hyperuricemia,Aldosterone
excess,supressed renin levels in 60% cases
 CKD, Albuminuria,
 Higher Framingham 10-year risk score
 High salt intake
ETIOLOGY OF RH

 IDENTIFYING AND CORRECTING MEDICATION NON

ADHERENCE
 NON ADHERENCE –(Because will avoid unnecessary and
potentially harmful treatment intensification also a
confounder in RH)

 INDIRECT METHODS-patient self-report EXCELLENT

COMMUNICATION SKILLS
 medication adherence assessment tools
1. Morisky Medication Adherence Scale
2. Hill-Bone Compliance Scale

 DIRECT METHOD –Blood or urine

POOR BP MEASUREMENT TECHNIQUE

 Proper BP measurement technique entails (AHA)

 (1) preparing the individual by emptying a full urinary bladder
and then sitting with legs uncrossed and back, arm, and feet
supported in a quiet room, ideally 5 minutes before the first
reading is obtained;

 (2) choosing a BP cuff with a bladder length of at least 80% and

width of at least 40% of the arm circumference;

 (3) placing the cuff directly on the skin of the upper arm at the
level of the heart on the supported arm; and

 (4) obtaining a minimum of 2 readings 1 minute apart.

 The inappropriately elevated cuff pressure in patients with

severe arterial disease has been called PSEUDOHYPERTENSION
( MEDIAL CALCIFICATION –INACCURATE DETECTION OF
KOROTKOFF SOUND)
[Link] STYLE FACTORS
 OBESITY-
Excess body fat ranks among the most important
factor responsible for the increasing prevalence
of hypertension

 Visceral adiposity in particular plays a

fundamental role in causing high BP.

 STUDY IN SPAIN (n-14461)Spanish Ambulatory

Blood Pressure Monitoring Registry, a BMI ≥30
kg/m2 was also an independent risk factor for RH
 High Sodium Diet
 Alcohol- Heavy alcohol intake (>30–50
g/d) is a well established risk factor for
hypertension
 Physical inactivity
 Dietary pattern
 smoking
[Link] related RH
 Nonsteroidal Anti-Inflammatory Agents-
 (NSAIDs) increase BP by reducing the production of
prostaglandins E2 and I2 , leading to reduced vasodilation
(afferent arterioles)and sodium excretion.

 The SBP increase with NSAIDs in ACE inhibitor from 5 to 10

mmHg.

 Celecoxib selective Cox2- has less effect on BP.

 NSAIDs Affects the treatment of diuretics, ACE inhibitors,

ARBs, and β-blockers.

 Antihypertensive medication interactions have typically not

been shown with CCBs
 Oral contraceptives raise BP and induce
hypertension by increasing
angiotensin biosynthesis.
 Estrogen replacement therapy and
hormone replacement therapy appear to
have a neutral effect on BP,since the
dose is less than OCP.
 Sympathomemetic agents –
 Amphetamine
 Ephidrine and pseudoephidrine
 Immunosuppressive Agents
 Cyclosporine - Cyclosporine and tacrolimus increase
BP by inducing systemic and renal vasoconstriction and
sodium retention.
 Rx-CCBs

 Other agents
 Recombinant Human Erythropoietin Long-term use of
erythropoietin promotes vascular smooth muscle cell
growth, vascular remodelling, and medial hypertrophy,
with maintained elevated Bp.
 TYROSINE KINASE INHIBITOR (VEGF)reduction of nitric
oxide and prostacyclin bioavailability, an increase of
systemic vascular resistance, and vascular stiffness
 Antidepressant – when consumed
with food containing rich in
tyramine( especially with
MAO– ,tranylcypromine ) eg; wine,
cheese
 Also TCA’s –venlafaxine, fluoxitine
SLEEP DISORDERS
 Sleep deprivation- defined <6 hours of
uninterrupted sleep

 Mechanism
 activation of both the sympathetic nervous
system and the renin-angiotensin-aldosterone
system.

 sleep duration < 5 hr in < 60 yr and

 sleep duration of > 9 hr in > 60 yr predisposes
to hypertension .

 If the patient is receiving diuretics and is not

adherent to a low-sodium diet, this will produce
nocturnal micturition and result in interrupted
sleep.
[Link] (Obstructive sleep apnea)

 High occurrence of OSA in patients with RH

has been attributed to increased fluid
retention and accompanying upper airway
edema( mineralocorticoid excess & high
salt intake )
 OSA - the increase in sympathetic activity
IS DUE TO intermittent hypoxia
 OSA-associated hypertension is only
slightly reduced by continuous positive
airway pressure (CPAP) treatment( 2 – 5
mmhg)
 Poor bp control in AHI >30/hr
 Preffered Rx – spiranolactone
[Link] Hypertension: Diagnosis
and Management

[Link] Aldosteronism-
 Group of disorders in which aldosterone
production is inappropriately high, and
independent of the renin-angiotensin system
and in which aldosterone secretion is not
suppressed by sodium loading.
 Prevalence – 20% in confirmed RH
 Clinical features - volume expansion and
sympathetic nervous system activation,
hypokalemia, metabolic alkalosis, and advanced
cardiovascular and renal disease

SCREENING for primary aldosteronism

 (aldosterone/renin ratio [ARR]) from a blood

sample obtained in the Morning
 A positive screening test requires an ARR of
>30 or >20 if plasma aldosterone concentration
is ≥16 ng/dL

 Prerequisite –
 correction of hypokalemia
 antimeneralocorticoids withdrawn for 1 month
 Beta blockers , alpha 2 antagonist , ACE -,
ARBs , DHP for 2 wks

 Preferred agents – verapamil, alpha 1

 Confirmatory test –

 saline suppression test, oral salt-loading test,

captopril test, or fludrocortisone suppression test.

 Patients with unilateral disease (50%; aldosterone-

producing adenoma or, much less frequently,
unilateral hyperplasia) respond to unilateral
laparoscopic adrenalectomy with complete cure
(≈50%)

 Patients with bilateral disease (idiopathic

hyperaldosteronism) usually have marked
improvement in hypertension control with
spironolactone or eplerenone
[Link] parenchymal disease
 Most common cause of secondary hypertension (2-5%)
 Most common cause of CKD: DM and HTN (>chronic
glomerulonephritis)
 HTN is present in >80 patients with CKD
 2/3 CKD patients: nocturnal masked HTN
 More severe in glomerular than interstitial diseases

To figure out the primary disease:

 Proteinuria>1g/d
 Active urine sediment
Indicate primary renal disease

 Goal of treatment: control BP and retard progression of

renal disease
 Most need: ACE inhibitor/ARB + Diuretic + CCB
[Link] disease
 Goldblatt hypertension (two
basic models)

 1.1 clip 2 kidneys

 The ischemic kidney secretes
renin, ↑ANG II →↑(BP). As BP
rises,↑ pressure natriuresis
from the contralateral
kidney ;no sodium retention.

 2. 1 clip 1 kidney
 contralateral kidney is
removed. In this case the
pressure natriuresis can no
longer occur, and sodium
retention occurs→low renin
 Renal artery stenosis

 Most common in older age group

 24% of older subjects (mean age, 71 years) with RH have
significant renal arterial disease.
 Mechanism – reduced blood flow –activates RAS
 Most patients with renovascular disease tolerate ACE inhibitor
or ARB therapy without adverse renal effects

 The rise in serum creatinine during treatment in patients with

renal artery stenosis or CKD is often transient and is greater if
intravascular volume drops with diuretics or ACE
Inhibitors ,system blockers, which dilate the renal efferent
more than the afferent arteriole.
 Classification:
 (1) Atherosclerotic renal artery stenosis
(85%): origin of renal artery, older
patients
 (2) Fibromuscular disease: distal 2/3 and
branches of the renal arteries;
women(20-60 years)
 (3) Emboli in renal arteries
 (4) Extrinsic compression of renal
arteries
 MANAGEMENT:

 Screening test: Duplex USG, (75% sensitive and 90%

specific)
 Confirmation: Spiral CT or MR angiography (beware in
advanced CKD) or DSA
 FMD:
 Rx of choice: Balloon angioplasty without stenting
(excellent outcome)
 ARAS:
 Conservative approach: Control cardiovascular risk
factors Smoking cessation; statins and antiplatelet
drugs ACEI- or ARB for HTN
 Indications for stenting:
 (1) Intractable hypertension,
 (2) AKI induced by ACEI or ARB
 (3) Recurrent, episodic (flash) pulmonary edema.
[Link]/Paraganglioma
 Chromaffin cell tumors
 The prevalence is likely higher in patients
referred for RH ( up to 4%)
 Symptoms
 paroxysmal hypertension (which may be
sustained in up to 50% of those with high
norepinephrine production) or
 orthostatic in epinephrine-predominant tumors
 Headache, palpitations, pallor, and
piloerection (“cold sweat”).
screening test of choice
 urine metanephrine from the tumors, measured as plasma free
(sensitivity, 96%–100%; specificity, 89%–98%)

 Elevated levels are also seen in OSA, Obesity and patient using
TCAs – levels are usually <4 times upper limits

 Imaging should be pursued only after biochemical evidence for a

pheochromocytoma has been obtained.

 The recent Endocrine Society guideline recommends starting

with CT, with magnetic resonance imaging

 Metaiodobenzylguanidine scanning to further evaluate

suspected metastatic disease

 α-adrenergic blockade, a high-sodium diet, and fluid intake are

recommended for at least a week before surgery to prevent
intraoperative BP instability and to reverse volume contraction
from pressure-natriuresis.
[Link] SYNDROME

Excessive glucocorticoid exposure from endogenous or exogenous
sources.
 Mechanism -excessive activation of mineralocorticoid receptor
 Although high BP (perhaps even severe forms) may be common among
patients with Cushing syndrome,BUT its prevelance in RH is less.
 Classical symptoms
 mood disorders,
 menstrual irregularities,
 muscle weakness
• signs
 weight gain,
 abdominal striae,
 hirsutism,
 dorsal and supraclavicular fat,
 fragile skin
 Treatment – mineralocorticoid antagonist eg spiranolactone and
eplerenone
[Link] of the
Aorta
 Patients with operated coarctation of the aorta are
likely to have hypertension in adulthood
 Due to exaggerated BP response to exercise.
 If H/O repair in past - gradient between the right
arm and leg is present-CT angio for residual
disease.
 Rx – Persistant hypertension = beta blocker + Ace
inhibitor
 If resistant to treatment, surgical or catheter based
intervention should be considered if the risk/benefit
ratio for the contemplated procedure is favorable
Evaluation of RH
 The evaluation of patients with RH
should be directed towards
 Confirmation of true treatment
resistance,
 Identification of causes contributing to
resistance (including secondary causes
of hypertension)
 Documentation of complications of the
hypertensive disease process
 Physical Examination:
 • Body habitus
 • Blood pressure in both arms(<30yr) -If the thigh SBP is
>10 mmHg lower than the arm SBP while the patient is
supine, imaging studies for coarctation should be
performed.
 • Supine and standing blood pressures
 • Funduscopic examination of retina
 • Vascular and abdominal bruits
 • Cardiac rate and rhythm
 • Signs of congestive heart failure
 • Signs of secondary hypertension
Management of RH
 Lifestyle modification
 Weight loss
 >5% weight reduction in overweight
 >10% weight reduction in obese , will lower 4.5/3.2
mmhg in hypertensive

 Dietary salt restriction

 1-g (43.5-mmol) reduction in daily sodium intake
produces a 2.1–/1.2–mmHg will decrease in SBP
 AHA recommends sodium intake to 2.4 g for patients
with RH , stringent restriction <1.5g on case by case
basis
 DASH diet and other dietary factors

 Alcohol -< 10g/d in women , < 20g/d in male

 high potassium diet
Caution in CKD stage 4 & 5
 Diet rich in fruits , vegetables low fat diary products with reduced saturated and
total fats
 For a 2000 kcalorie DASH diet
 Grains :6-8 servings/day
 1 serving is one slice of bread,1ounce dry cereal,1/2 cup cooked cereal,rice or
pasta
 Vegetables:4-5 /d
 1 serv is 1 cup raw leafy green vegetable,1/2 cup cut-up raw or cooked veg,or ½
cup vegetable juice
 Fruits :4-5 /d
 1 serv is 1 medium fruit ,1/2 cup fresh,frozen or canned fruit,or ½ cup fruit juice
 Fat free or low fat dairy products: 2-3/day
 1 serv is 1 cup milk or yogurt, or 1/2 ounce of cheese
 Lean meat ,poultry & fish :six 1 ounce servings for fewer a day
 1 serv is 1 ounce cooked meat ,poultry or fish or 1 egg
 Nuts seeds legumes :4-5 servings/wk
 1 serv is ½ cup nuts, 2 tablespoon peanut
 EXERCISE
 Endurance exercise(aerobic)EG-
swimming ,running walking
 –8.3/4.5 lowered BP

 Dynamic resistance exercise EG-push

up ,bench press
 reduced BP by1.8/3.2 mmHg among
hypertensive patients
 AHA GUIDELINES FOR EXERCISE
 ≥150 min/wk (in 3–5 sessions of 30–40 min) of moderate
to intense aerobic activity, optimally supplemented with
2 to 3 sessions of light resistance training per week.

 Because RH is more common in obese and older adults,

some may be unable to achieve moderate to intense
aerobic activity.

 ALTERNATIVE APPROACH - meditation, device-guided

slow breathing, and isometric handgrip exercise, were
felt to hold promise for clinical practice
 PHARMACOLOGICAL TREATMENT FOR RH

 GENERAL PRINCIPLES
1. Rule out white coat effect & masked
uncontrolled hypertension
2. 3 drugs should already been prescribed
(CCBs , ACE - /ARBS, Diuretics)
3. Diuretics are choosen based on Egfr
Diureticsand
of disease.
eGFR(Ml/ DRUGS MAX
choice min/1.73 m2) TOLERATED
Hydrochlorothi 45 DOSE
azide AMLODIPINE 10MG
chlorthalidone 25-30
chlorthalidone 25MG
Torsemide <30 or in
hypoalbumine RAMIPRIL 20MG
SPECIFIC THERAPEUTIC MANAGEMENT

 The diuretics with the greatest evidence base for reducing

cardiovascular outcomes are the thiazide-like diuretics
chlorthalidone and indapamide(AHA)

 Calcium channel blocker(DHP) – amlodipine and Nifedipine

 long-acting formulations of Nifedipine may have slightly
greater antihypertensive actions than amlodipine but are
associated with more edema.
 Verapamil – no evidence in RH

 Using divided doses of drugs with half-lives of<12-15hrs

may also improve BP control ,even when the drug has
theoretically has action for 24 hrs.
 Choice of 4th drug
 Patient not in overtly volume overload but low renin
status or salt sensitivity of BP, (mineralocorticoid
receptor antagonists)
 RX-spironolactone or eplerenone
 Spiranolactone can be given OD dose
 Disadvantages
 Hypekalemia k+ >4.5
 Egfr<45
 Males –gynecomastia and erectile dysfunction
 Females – menstrual irregularities
 Less with eplerenone ,shorter t1/2, but BD dosing
 Choice of 5th drug –symapthetic drive
If HR>70 Bpm consider Betablockers
If beta blockers are contraindicated
 central α-2 agonists, transdermal

clonidine or guanfacine should be

considered
 Choice of 6th drug
 Hydralazine
 If Heart failure –Hydralazine +isosorbide dinitrate (isolazine)

 restore Ca2+ cycling and cardiac contractile performance and

control superoxide production in isolated cardiomyocytes.
 Moreover, Hydralazine reduces nitrate tolerance.

 Hydralazine increases sympathetic tone and sodium avidity hence,

has to be used with betablocker and diuretics

 Choice of 7th drug

 Substitute minoxidil 2.5mg BD or TID for hydralazine
 Requires concomitant use of beta blocker and diuretics
Device-Based Treatment of RH

 1940s, surgical sympathectomy(lumbar

sympathectomy) demonstrated
improvement in BP control & reduction in
cardiac size, improved renal function &
cvd events before the availability of
antihypertensive drugs.
 Side effects –
 severe orthostatic hypotension,
 erectile dysfunction and bowel and
bladder incontinence
 [Link] Nerve Ablation
 Widely studied in Europe and Australia
 SYMPLICITY HTN-3 trial,
 Sham-controlled study
 showed little to no effect of renal denervation therapy in severely drug
treatment–resistant population.
 Drawbacks
 methodological concerns,
 Inadequate denervation resulting from technical failure of the catheter

 DENERHTN trial (Renal Denervation for Hypertension)

 Demonstrated a statistically significant reduction in daytime
ambulatory SBP (−5.9 mmHg; P=0.03) in patients on 3
antihypertensive drugs.

 At present, renal denervation procedures to treat RH have been

discontinued in most countries unless patients are in research
programs.
[Link] Baroreceptor Activation
Therapy
 Baroreflex activation leads placed adjacent to
the carotid sinus, an implantable pulse
generator, and an external programming system.
 Reduced sympathetic nervous system activity
and enhanced vagal activity.
 HR decreases, allowing greater left ventricular
filling time and reducing cardiac workload and
energy.
 In addition, arterial dilation inturn reducing
cardiac afterload and improving renal blood flow,
which increases natriuresis
 The MobiusHD carotid bulb expansion
device is a small endovascular implantable
device that works by stretching the carotid
artery at the bulb and activates
baroreceptors to lower BP.
 CALM-FIM_EUR(Controlling and Lowering
Blood Pressure With the MOBIUSHD)
 Has recently demonstrated in patients with
RH that endovascular baroreflex amplification
with the MobiusHD device substantially
lowered BP with an acceptable safety profile.
REFERENCES
 HARRISONS Principles of Internal
Medicine -21ST EDITION
 Braunwald’s Heart disease: A text book
of cardiovascular medicine
 2018 ESC/ESH Guidelines for thee
management of arterial Hypertensio
 [Link]
.1161/HYP.000000000000008
THANK YOU