Definition of RHT

As one of the main criteria for RHT is having BP levels above target, we might observe slight differences in the available definitions for RHT in the latest published guidelines. In the 2017 AHA/ACC, 2018 European Society of Hypertension (ESH/European Society of Cardiology) and 2020 International Society of Hypertension hypertension guidelines, the goals to consider BP as controlled are SBP levels below 140 mm Hg in European and international guidelines and below 130 mm Hg in North American guidelines. The goals for DBP are below 90 mm Hg in European and international guidelines and below 80 mm Hg in North American guidelines.3–5

The 2018 AHA scientific statement on detection, evaluation and management of resistant hypertension defines RHT as the condition where the BP values of a patient with hypertension remain elevated above target despite concurrent use of three antihypertensive agents of different classes, commonly including a long-acting CCB, a renin-angiotensin system (RAS) blocker (an ACE inhibitor or angiotensin receptor blocker) and a diuretic. All agents should be administered at maximum or maximally tolerated doses and at the appropriate dosing frequency. Patients with the white coat effect should not be included in the definition of RHT, and the diagnosis of RHT requires the exclusion of non-adherence to antihypertensive medications. Finally, this position paper also includes patients with RHT whose BP shows values below target but are on four or more antihypertensive medications, a condition that has been referred to in the literature as controlled RHT.7

In the 2023 ESH guidelines, RHT is defined as hypertension in patients who fail to lower office BP to ESH treatment goals (BP levels below <140/90 mm Hg) once appropriate lifestyle measures and treatment with optimal or best tolerated doses of three or more drugs (specifying a thiazide/thiazide-like diuretic, an RAS blocker and a CCB) have been initiated. The ESH guidelines also specify that inadequate BP control should be confirmed by out-of-office BP measurements showing uncontrolled 24-hour BP (130 mm Hg SBP or 80 mm Hg DBP) values. Evidence of adherence to therapy and exclusion of secondary causes of hypertension are required to define RHT, otherwise RHT is only apparent and called pseudo-RHT.8

The guidelines therefore recommend thoroughly confirming uncontrolled office BP values through measurement of BP values outside of the office as ambulatory BP measurement (ABPM) or home BP measurement (HBPM), confirming adherence to therapy and properly ruling out secondary causes of hypertension when RHT is suspected in order to have a case of true RHT. Pseudo-RHT is the condition where office BP shows lack of BP control, while ABPM or HBPM shows well-controlled BP. Nevertheless, if obtaining ABPM or HBPM is not feasible, epidemiological studies refer to this condition as apparent RHT. On the other hand, in some patients, office BP values are below target, showing good control, but ABPM or HBPM values are clearly showing lack of BP control. This condition is called masked RHT.9 Finally, refractory HT is a type of RHT where BP remains uncontrolled despite being on five or more antihypertensive drug classes, including a diuretic.

Epidemiology of RHT

It is difficult to learn the actual prevalence of RHT due to several reasons. First, the prevalence of RHT depends on the BP levels used to define BP control in the various guidelines.3–5 Moreover, although the guidelines clearly establish how to rule out pseudo-resistance, population studies do not always exclude it.3–5 For example, Noubiap et al10 conducted a meta-analysis of 91 studies reporting data of a pooled sample of 3 207 911 patients with hypertension on antihypertensive drugs globally to estimate the global prevalence of RHT. Nevertheless, the first limitation was that 64% of the studies only used office BP measurement. They found a prevalence of apparent treatment resistance of 14.7%, but only 10.3% for true RHT. True RHT was found in 22.9% of patients with CKD, 56.0% of renal transplant recipients and 12.3% of geriatric individuals. Another recent study found that in Canada 5.3% of subjects with hypertension had apparent RHT. The majority were female and aged 70 or older (45.3%).11

As for the evolution of prevalence over time, according to a longitudinal study from the UK (1996–2004), the incidence of RHT among patients with hypertension increased from 0.93 per 100 patient-years to 2.07 per 100 patient-years.12 Finally, selection bias is usually present in registries and clinical trials and therefore could explain the higher prevalence of apparent RHT.

Outcomes of RHT

According to observational studies, people with RHT are more likely to have adverse CV outcomes than those without RHT. In a retrospective analysis of 6357 adult participants with hypertension in the National Health and Nutrition Examination Survey, those with RHT had a 47% higher risk of mortality, myocardial infarction, HF, stroke or CKD after a median follow-up of 3.8 years.13 Another study using data from subjects with hypertension from Kaiser Permanente Southern California Health Care compared the risk of renal, CV and mortality outcomes among individuals identified with controlled RHT, uncontrolled RHT and non-RHT. They found that those with RHT had a 32% higher possibility of acquiring end-stage renal disease, a 24% higher risk of an ischaemic cardiac event, a 46% higher risk of HF and a 24% higher risk of an ischaemic stroke.14

Diagnosis of RHT

For an accurate and proper diagnosis of true RHT following major guideline recommendations, it is recommended to take the steps that are summarised in figure 1.

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Figure 1

Diagnostic algorithm proposal for resistant hypertension. BP, blood pressure; CKD, chronic kidney disease.

As a first step, the causes of pseudo-RHT must be ruled out, which are summarised in table 1. Pseudo-RHT may be due to errors in BP measurement. For instance, the patient’s preparation, the office’s milieu, wrong cuff size and improper BP measurement methodology can significantly affect measurements.15

Beside accurate office BP measurement, home, work or ambulatory BP readings should always be obtained to exclude the white coat effect,4 which could occur in 30% of patients with elevated BP and with treatment of up to three drugs.16 Particularly for office BP measurements and due to intrinsic BP fluctuations, diagnostic BP records should comprise an average of at least two measurements taken on at least two different dates. As for out-of-office BP measurement, either an HBPM or a 24-hour ABPM is recommended.17

Before diagnosing RHT, non-adherence to prescribed antihypertensive drugs also has to be ruled out. Patients with pseudo-RH have a high prevalence of non-adherence as some patients are reluctant or unable to adhere to their antihypertensive medications.18 While the WHO estimates the prevalence of non-adherence to antihypertensive medication at between 30% and 50%,19 the estimated prevalence of non-adherence to antihypertensive medication in Asia is 48%.20 Significant pill burden, complicated dosing, high cost, high frequency of adverse reactions with multidrug antihypertensive regimens and poor patient–clinician relationships are all factors that contribute to non-adherence, causing pseudo-RHT. Direct observed therapy clinic can be an effective method for identifying the patient with truly resistant hypertension.18 Medication non-adherence is a significant problem in a patient with apparent RHT. Identifying the most accurate and clinically feasible adherence assessment methods is necessary to reduce BP and CV morbidity, facilitate early behavioural intervention, prevent unnecessary diagnostic testing, and limit the sometimes unnecessary and expensive BP-lowering procedures.21

Finally, it is mandatory to discontinue or minimise interfering substances such as steroidal and non-steroidal anti-inflammatory drugs, and sympathomimetic drugs such as amphetamines, decongestants, stimulants, oral contraceptives, licorice and Ephedra, which can increase BP.4

Once pseudo-RHT has been ruled out, it is mandatory to also rule out secondary hypertension, as these patients usually show an RHT clinical picture. As can be seen in table 2, the frequent causes of secondary hypertension are primary hyperaldosteronism, pheochromocytoma, obstructive sleep apnoea (OSA), renal artery stenosis and renal parenchymal disease, while the less frequent causes are Cushing’s syndrome, thyroid and parathyroid diseases, and fibromuscular dysplasia. Although secondary hypertension might present frequently as RHT, its diagnosis, treatment and outcomes are completely different and therefore it needs to be ruled out before establishing a diagnosis of RHT.16 The most relevant and frequent secondary hypertension causes that have to be considered are primary aldosteronism in patients with an elevated aldosterone to renin ratio; CKD when the estimated glomerular filtration ratio (eGFR) is <60 mL/min/1.73 m²; renal artery stenosis in young female patients, or known atherosclerotic disease with worsening kidney function; and OSA in patients with snoring, witnessed apnoea and excessive daytime sleepiness. As for the less frequent causes, fibrodysplasia can be considered in young female patients with hypertension, and pheochromocytoma in patients with episodic hypertension, palpitations, diaphoresis and headache.4

Treatment

RHT treatment should involve lifestyle changes, including reduced sodium and alcohol intake, regular physical activity, weight loss as shown by the TRIUMPH RCT (Lifestyle Interventions in Treatment-Resistant Hypertension) and discontinuation of interfering substances4 22; however, current treatment should also be rationalised, accompanied by sequential addition of antihypertensive drugs to triple therapy.4 8 23

In addition to lifestyle recommendations, a specific pharmacological treatment strategy is suggested (figure 2).

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Figure 2

Treatment algorithm proposal for resistant hypertension.

The algorithm in the 2023 ESH guidelines recommends the use of single pill combination (SPC) treatment as the basis. Replacing current drugs with a more appropriate and less difficult treatment regimen based on the patient’s age, ethnicity, compelling grounds for certain medication classes, comorbidities and risk of drug–drug interactions is recommended. Drugs should be provided at the maximum tolerated dose and in SPCs to improve adherence to therapy. It is also recommended to increase the thiazide diuretic dose or switch to a longer-acting thiazide-like diuretic. If the eGFR is less than 30 mL/min, administer loop diuretics instead of thiazide/thiazide-like diuretics. Nevertheless, the CLICK (Chlorthalidone in Chronic Kidney Disease) trial found chlortalidone reduced the 24-hour SBP in patients with stage 4 CKD with poorly controlled hypertension.24 Furosemide and bumetanide should be given two times per day due to their short duration, while longer-lasting drugs such as torsemide can be given once daily. Severe CKD and albuminuria may require increased loop diuretic doses. Monitoring kidney function, electrolyte levels and fluid status is crucial to detect dehydration, hypokalaemia, hyponatraemia, hypovolaemia or worsening renal function.8

The fourth line of treatment for patients with RHT should include the mineralocorticoid receptor antagonist (MRA) spironolactone, as demonstrated in the PATHWAY-2 (spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension) trial and meta-analyses, including those with heart failure with reduced ejection faction (HFrEF). A secondary analysis of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial showed beneficial effects in patients with heart failure with preserved ejection faction (HFpEF), a condition with difficult-to-control hypertension. The efficacy and safety of spironolactone in patients with advanced CKD or higher potassium levels at baseline have not been established. The risk of hyperkalaemia is greater in patients with CKD, especially if the drug is added to a treatment regimen that usually includes an RAS blocker. It is necessary to closely monitor plasma potassium and eGFR after treatment initiation and at least annually or at 3-month to 6-month intervals thereafter. Newer potassium binders such as patiromer and sodium zirconium cyclosilicate can reduce the risk of hyperkalaemia without increasing sodium overload or decreasing antihypertensive drug absorption.25

Spironolactone is not suitable for all patients due to its antiandrogenic side effects, such as breast tenderness, gynecomastia, sexual impotence and menstrual irregularities. Eplerenone, a less potent alternative, can lower BP but is only approved for patients with hypertension in some European countries. Amiloride can be used at high doses. New, selective non-steroidal MRAs such as finerenone, esaxerenone and ocedurenone may provide future alternatives to spironolactone for patients with RHT. Selective aldosterone synthase inhibitors such as baxdrostat have been shown to effectively lower BP in patients with RHT, potentially becoming an additional treatment.26 Spironolactone and other MRAs should be used cautiously in patients with reduced eGFR and baseline potassium levels above 4.5 mmol/L. Alternatives include bisoprolol, doxazosin extended release or alpha-adrenergic receptor agonists such as clonidine. However, bisoprolol and doxazosin reduced BP less effectively than spironolactone in the PATHWAY-2 trial, while clonidine showed similar BP-lowering effects in a head-to-head comparison open-label RCT.27 The dual endothelin antagonist aprocitentan may also be used as it has a sustained BP-lowering effect in patients with RHT.23

Recent RCTs have demonstrated that endovascular renal denervation (RDN) can significantly reduce BP in patients with uncontrolled hypertension. In a large registry of patients with RDN, BP reduction was long-lasting and without significant safety problems. RDN can be proposed as an adjunctive therapy for patients with RHT, provided the eGFR is >40 mL/min/1.73 m², where BP control cannot be achieved or serious side effects cannot be avoided with antihypertensive medications. However, dedicated trials such as PATHWAY-2 and ReHOT (Resistant Hypertension Optimal Treatment) showed short-term efficacy, with a large fraction of patients still not controlled after treatment with spironolactone. Therefore, as for device therapy, more specific studies are needed before any device-based antihypertensive treatment can be generalised into routine clinical practice. Until then, the use of these devices should be limited to specialised centres. A more detailed view of these trials is shown in table 3.

Treatment for RHT considers patients’ frequent comorbidities, and additional treatment options are also offered. Continuous positive airway pressure (CPAP) may be beneficial in patients with OSA, while glucagon-like peptide-1 (GLP1) receptor agonists can reduce body weight and improve CV prognosis in obese patients. Bariatric surgery can lower BP, CV risk factors and CV events in severely obese patients. Sodium-glucose transport protein 2 (SGLT2) inhibitors may add a moderate BP-lowering effect to background antihypertensive therapy. The sacubitril–valsartan combination did not lower hospitalisation for HF and death in patients with HFpEF but significantly reduced the New York Heart Association (NYHA) class. It also reduced BP in patients with RHT despite treatment with four antihypertensive drugs, confirming the BP-lowering effect of the compound in a phase II trial.28 The use of SPC treatment is the basis for replacing current drugs with a more appropriate and less difficult treatment regimen based on the patient’s age, ethnicity, compelling grounds for certain medication classes, comorbidities and risk of drug–drug interactions.

According to the AHA/ACC recommendations, diuretic medications should be intensified in RHT and an MRA should also be added. Additionally, other available drugs with a different mechanism of action should be considered. Finally, the guidelines urge patients with CKD and/or those treated with powerful vasodilators to use loop diuretics to reduce BP.4

The AHA scientific statement on RHT also points to some specific issues that are associated with treatment resistance and recommends some management considerations. If patients present issues related to volume control and need resolution of oedema, a switch in diuretics from a thiazide to a chlorthalidone or even to a loop diuretic would be advisable. If heart rate control is inadequate, beta-blocker, alpha beta-blocker, verapamil or diltiazem could be used. In patients with low renin and aldosterone levels, a low-salt diet, avoiding night-time shift work and amiloride could be recommended. However, in case of low renin levels but normal to high aldosterone levels, it would be reasonable to use MRAs. It is recommended to evaluate BP patterns according to home and ambulatory BP monitoring to decide if split dosing of medications would improve control. If medication adherence is questionable, the statement recommends initiating indirect or direct methods to identify non-adherence, and if partial or complete non-adherence is documented it is recommended that the issue be discussed frankly and non-judgementally with the patient and the family. In case of sleep disordered breathing and significant anxiety associated with highly variable hypertension, initiating non-drug strategies concurrently with or separately from antihypertensive drug therapy is recommended.15 In one study, a multifaceted pharmacist intervention through medication possession ratio in a hospital setting led to a sustained improvement in medication adherence in patients with hypertension.29

The ISH recommendations advise using maximum tolerated dosages of diuretics, specifically thiazide-like rather than thiazide diuretics, and loop diuretics in patients with eGFR <30 mL/min/1.73 m² or clinical volume overload to optimise therapy. As with previous recommendations, adding a low dose of spironolactone as a fourth-line medication is advised if serum potassium is below 4.5 mmol/L and eGFR is higher than 45 mL/min/1.73 m². Amiloride, doxazosin, eplerenone, clonidine and beta-blockers are suggested as spironolactone alternatives, along with any other antihypertensive drugs not already in use.5

The different recommendations for RHT following different guidelines are summarised in table 4.