Selecting patients for interventional procedures to treat hypertension

Figures & data

Table 1. Work up pathway for selection of hypertensive patients for interventional therapy.

Steps in patient selection	Rationale for approach
1. Identify patients for whom device therapy of hypertension seems appropriate
Patient with uncontrolled HTNCould be unmedicatedMay be uncontrolled taking 1-2 drugsMay have resistant hypertension	Interventional therapy should be available to the following:Not keen to take medsPrepared to take meds & have RDNUnable to take meds due to drug intolerances
2. BP measurement to confirm hypertension Uncontrolled hypertension should be confirmed in the out of office setting before considering RDN
Office BPABPMHome BP	Important starting point: does not exclude white coat or masked HTN GOLD STANDARD To confirm daytime and night-time BP levels Where ABPM not available, critical to confirm out of office hypertension
3. Lifestyle & Medication optimisation
High fruit and vegetable (Mediterranean) dietSalt restrictionIncreased dynamic cardiovascular exerciseWithdraw drugs that cause hypertensionImprove adherence to antihypertensive medication	BP lowering effects similar to monotherapy [14] Aim for <5-6 g per day, (see also section 3A)Prevents hypertension & lowers BP, reduces CV morbidity & mortality [15 ](See paper by Sudano et al) Depends on access to resource such as SPC therapy. (See section 3B)
4. Screen for secondary hypertension(see Figure 1)(can be done in conjunction with step 2 to minimise delay in offering procedure and de-risking patient)
Renal parenchymal or renovascular hypertensionEndocrine hypertensionObstructive sleep apnoeaAortic coarctation	Common in both children and adults [16]. (See also section 4A)Includes common and rare causes of hypertension (See also Section 4B)Common in patients with resistant hypertension (see also Section 4C)Second most common cause of hypertension in children Screen with echocardiogram, also MRA or CTA aorta can be used [17]
Uncontrolled hypertension confirmed and lifestyle & medication optimised,no reversible secondary cause of hypertension identifiedDocument HMOD MDT Discussion - PROCEED TO RDN

BP: blood pressure; ABPM: Ambulatory BP monitoring; RDN: renal denervation; SPC: single pill combination; CV: cardiovascular; MRA: magnetic resonance angiogram; CTA: computed tomography angiogram; HMOD: hypertension-mediated organ damage; MDT: multidisciplinary team.

Table 2. Thresholds for diagnosis & treatment of hypertension with out of office monitoring.

Category	Office	Ambulatory	Home	Office	Ambulatory	Home
	Threshold for hypertension diagnosis			Treatment targets
SBP (mmHg)	≥ 140	≥135 (awake) ≥120 (asleep) ≥120 (24 H mean)	≥ 135	Age 18–64. < 130Age 65-79. <140 < 130 where toleratedAge 65-79 with ISH. < 140-150 < 130–139 if tolerated Age ≥80 < 140-150	Not stated	Not stated
DBP (mmHg)	≥ 90	≥ 85 (awake) ≥ 70 (asleep) ≥120 (24 H mean)	≥ 85	< 80	Not stated	Not stated

Adapted from the 2023 ESC/ESH Hypertension guideline [20].

SBP: systolic blood pressure; DBP: diastolic blood pressure 24 H, 24 h; ISH: isolated systolic hypertension.

Table 3. Pitfalls in the use of ABPM and options to solve them.

Pitfalls	Solution
ABPM is not always easily accessible. Global uptake has been variable and often limited through lack of reimbursement and in poorer geographies there may be no access at all.	Home BP monitoring is an acceptable alternative where ABPM not available
ABPM is obtrusive during the day Cuff inflation optimally occurs every 20 minutes during the day - patients undergoing a study during a working day may be inconvenienced. This may result in cuff alerting or even removal by the patient.	Consider setting daytime measurement interval to every 20-30 minutes. Permit wearer to remove monitor temporarily for unavoidable reasons (e.g. important meeting)
ABPM is poorly tolerated overnight Nocturnal cuff inflation ideally takes place every 20 minutes and, in some individuals, this is a cause of sleep disruption and nocturnal hypertension and loss of prognostic significance of the night time BP [30].	Consider setting nocturnal measurement interval to every 60 minutes Be aware that elevated nocturnal BP may represent alerting to cuff inflation although sleep disordered breathing (obstructive sleep apnoea) is also a cause
Correct programming for day/night is critical For instance, a night shift worker will have a very different day/night pattern compared to someone who sleeps overnight and this must be taken into account in the acquisition and reporting of their data.	Ensure a standardised operating procedure (SOP) for ABPM fitting that mandates programming according to each individual’s sleep/wake cycle
Intra-individual short-term reproducibility of ABPM is poor For example, an ABP monitor fitted on a busy working day may show higher values than one fitted on a weekend but the five weekdays are more representative of the total BP load than two weekend days.	ABPM daytime mean should be compared to home BP average where possible. Monitor should be fitted on a day that is representative of a normal pattern for the individual

ABPM: ambulatory blood pressure monitoring.

Table 4. Pitfalls in the assessment of salt intake.

Pitfalls	Solution
Commonly used methods to estimate sodium intake (24-hour dietary recall, food frequency questionnaire and food diary), have limited utility and tend to underestimate salt consumption [42]	Biochemical assay of urine is the most accurate way to record salt intake as up to 90% of consumed sodium is excreted in urine [43]
Spot urine electrolytes is not a reliable guide to salt ingestion	a 24-hour urine electrolyte assay is the gold standard method to estimate salt intake
24-hour urine collection underestimates salt intake insensible losses in sweat which will increase in hotter climates [44].	Assume salt loss of up to 1g a day due to sweating and more in hot climates

Table 5. Pitfalls in Assessing & managing adherence.

Pitfalls	Solution
Assessing drug adherence can be time consuming and is costly and current non-biochemical methods (e.g. questionnaires, pill counting, prescription refill data, electronic diaries and directly observed therapy) all have significant drawbacks [48]	Mass Spectrometric analysis of plasma/urine samples is the current gold standard to assess adherence [49]
Measurement of drugs/metabolites in plasma/urine gives only limited information due to the dynamic nature of adherence [50]	Increased research utilising mass spectrometry techniques is required and will inform future use of these technologies to evaluate adherence and plan treatment approaches
Current methods of improving medication adherence for chronic health problems are mostly complex and not very effective [51]	Simplify antihypertensive medication regimen as much as possible: use a SPC formulation where possible with once daily dosing

SPC: single pill combination.

Figure 1. Summary of causes of secondary hypertension and key screening investigations. A:CR: albumin:creatinine ratio; Ca: calcium; CKD: chronic kidney disease; CTA: computed tomography angiogram; DUS: duplex ultrasound; eGFR: estimated glomerular filtration rate; FHx: family history; LDDS: low dose dexamethasone suppression test; OSA: obstructive sleep apnoea; pMets: plasma metanephrines; PTH: parathyroid hormone; TSH: thyroid stimulating hormone; TTE: transthoracic echocardiogram; US: ultrasound.

Table 6. Clinical features suggestive of secondary hypertension.

Clinical feature	Description
Hypertension in childhood	Hypertension of any grade in children must always be investigated
Younger patients (<40 years) with grade 2 hypertension	Raises suspicion of a secondary cause especially in the absence of risk factors (family history/obesity/recreational drug use)
Acute worsening hypertension in patients with long standing stable normotension	Be mindful that other causes of BP increase should also be considered such as stress and medication non-adherence
More severe forms of acute or chronic hypertension	Resistant hypertension, Severe (grade 3] hypertension Hypertensive emergency (aortic dissection, hypertensive heart failure, stage IV hypertensive retinopathy, acute renal failure, eclampsia)
Presence of extensive HMOD	Left ventricular hypertrophy, hypertensive retinopathy, renal impairment, Arterial stiffening (increased pulse pressure and/or pulse wave velocity)
Clinical or biochemical features suggestive of secondary causes of hypertension (see also section 4A, 4B, 4C)	Coarctation of the aorta: differential BP between upper and lower limbs or between upper limbs (≥ 20/10 mmHg) Obstructive sleep apnoea: snoring, daytime somnolence, nocturia, obesity and increased neck circumference CKD: pallor, peripheral oedema Renovascular disorder: abdominal bruit, peripheral arterial disease Phaeochromocytoma: paroxysmal hypertension, palpitations, anxiety, or family history of phaeochromocytoma Cushing’s Disease: obesity, hirsutism, buffalo hump, diabetes, striae Hyperaldosteronism - hypokalaemia

HMOD: hypertension-mediated organ damage.

Table 7. Pitfalls in the assessment of renovascular disorder.

Pitfalls	Solution
DUS is highly operator dependent and has low sensitivity for detection of renal artery stenosis, especially in obese patients [58]	Where there is a high index of suspicion for RVD, cross sectional imaging techniques (with MRA/CTA) are preferred to DUS.
Appearances of renovascular lesion(s) using duplex US or cross-sectional imaging does not necessarily denote a functional stenosis	Further assessment with functional imaging such as Mag3 renography may be warranted Avoid use of plasma renin activity which is not of clinical value in RVD [58]
The diagnosis of FMD of the renal arteries should raise suspicion of disease in other vascular beds	Screening is recommended from brain to pelvis with CTA/MRA to document additional vascular tree involvement (e.g. cerebral aneurysm, Carotid artery dissection, visceral artery FMD) [59] Interventional treatment of FMD is with renal artery angioplasty (stent not required) and warrants input from a multidisciplinary team with vascular surgeon, interventional radiologist and nephrologist/hypertension specialists. The outcome may result in hypertension cure and the procedure may need to be repeated.
Atherosclerotic renal artery stenosis is a complex disorder	Interventional treatment of atherosclerotic renovascular disorder with renal artery angioplasty and stenting requires multidisciplinary team collaboration: interventionists and hypertension specialists +/- nephrologists. This should only be undertaken in centres of excellence Patients with isolated systolic HTN may be less likely to demonstrate a BP lowering response to renal stenting. Patients with resistant hypertension and atherosclerotic renovascular disease have increased arterial stiffness compared to those with primary hypertension [60]. In both the STAR and ASTRAL studies, grossly elevated Baseline pulse pressures (81 and 73 mmHg respectively, suggestive of severe arterial stiffness) may have been an important factor in the reduced BP lowering response to renal artery stenting [61,62]

DUS: duplex ultrasonography; RVD: renovascular disorder; MRA: magnetic resonance angiogram; CTA: computed tomography angiogram; MAG3 mercaptoacetyltriglycine-3 (a radionuclide isotope).

Table 8. Endocrine causes of hypertension.

Diagnosis	Prevalence in hypertension	Description	Work up
Primary Aldosteronism	5-15%	The commonest form of secondary hypertension and largely asymptomatic. Numerous subtypes identified (e.g. Familial Hyperaldosteronism Types I-IV) and increasing genetic basis identified [64]	Plasma electrolytes may show hypokalaemiaPlasma renin activity/mass, aldosterone levels24-hour urine for Na, K & aldosteroneConfirmatory tests (e.g. fludrocortisone suppression test or saline infusion test) CT or MRI adrenals
Cushing’s Disease	< 1%	Mostly arises from pituitary tumours but adrenal and ectopic sources also recognised [65]	Low dose dexamethasone suppression testing
Phaeochromocytoma	< 1%	Can be benign or malignant tumours of mostly adrenal origin but extra-adrenal origin recognised as well as hereditary forms (Multiple Endocrine Neoplasia, Von- Hippel Lindau, Hereditary paraganglioma) [66]	Plasma/urine fractionated metanephrinesCT or MRI abdomen & pelvis
Thyroid Disease	1-2%	Both overactive and underactive thyroid function are associated with hypertension	Thyroid function testsThyroid autoantibodies
Hyperparathyroidism	< 1%	Hypercalcemia is often asymptomatic unless very elevated Ca levels are present	Plasma calcium & parathyroid hormone levels CT neck

CT: computed tomography imaging; MRI: magnetic resonance imaging.

Table 9. Pitfalls in the assessment of hypertension of adrenal origin.

Pitfalls	Solution
Hyperaldosteronism is common but easily missed and complex to investigate and manage [70]	It is crucial to avoid interfering drugs to assay renin/aldosterone. This requires treatment with only verapamil and/or hydralazine and/or alpha blockers for 4 weeks prior to assay
ARR ratio is sometimes misleading as a screen	Up to 50% of ARR are falsely positive requiring confirmatory testing with saline infusion or fludrocortisone suppression testing False negative ARR arise in pregnancy and with hypokalaemia [71]
Adrenal venous sampling is required to prove lateralising autonomous aldosterone secretion if a surgical approach (adrenalectomy) is desired	This should only be done in specialised settings such as Hypertension centres of excellence or tertiary endocrine units
Cross sectional imaging (CT or MRI) will reveal adrenal nodules in 3-10% of all individuals:	mostly these are likely to be non-secretory (incidentalomas) but will require work up once detected [72]
Plasma/urine metanephrines can be falsely elevated [66]	Causes include anxiety & disease states (OSA, heart failure) Beware drugs that interfere with metanephrine assay – tricyclic antidepressants, monoamine oxidase inhibitors, stimulants (caffeine, nicotine)

ARR: aldosterone:renin ratio; CT: computed tomography imaging; MRI: magnetic resonance imaging; OSA: obstructive sleep apnoea.

Table 10. Pitfalls in screening for OSA.

Pitfalls	Solution
Not all hypertensive patients with OSA are obese [77]	Be alert to the possibility of OSA in young patients with no risk factors for hypertension and in any patient with loss of nocturnal dipping or reversed nocturnal dipping on ABPM [78]
Sleep scoring surveys have moderate diagnostic sensitivity and limited specificity for the diagnosis of OSA	When there is a high index of suspicion clinicians should proceed with HBST or PSG following a negative sleep survey and a positive survey should be followed up with confirmatory tests.

OSA: obstructive sleep apnoea; ABPM: ambulatory BP monitoring; HBST: home-based sleep test; PSA: polysomnography.

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