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Management Strategies for Treatment-Resistant Hypertension: Current Status and Future Outlook
Corresponding author: Indranil Dasgupta, Department of Renal Medicine, University Hospitals Birmingham, NHS Foundation Trust, UK, and School of Health Sciences, University of Birmingham, Birmingham, United Kingdom. E-mail: Indranil.Dasgupta@uhb.nhs.uk
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Received: ,
Accepted: ,
Abstract
Hypertension affects >1 billion individuals worldwide. Despite the availability of effective antihypertensive therapy, the prevalence of treatment-resistant hypertension (TRH), defined as uncontrolled hypertension despite the use of ≥3 antihypertensive agents at optimum doses, is reported to be 5 to 30% of the hypertensive population. Uncontrolled hypertension contributes to an elevated risk of stroke, myocardial infarction, heart failure, and kidney failure. TRH is associated with a 50% higher risk of cardiovascular disease than controlled hypertension. Several factors contribute to apparent treatment resistance, including poor medication adherence, physician inertia, inadequate doses or inappropriate combinations of antihypertensive drugs, excess salt and alcohol intake. The pathophysiology underlying true TRH remains unclear. In this article, we discuss the factors responsible for apparent treatment resistance in hypertension and the management strategies, including device therapy and newer antihypertensive agents that are likely to be available in the near future.
Keywords
Blood pressure
Drug adherence
Hypertension
Renal denervation
Resistant hypertension
Secondary hypertension
Introduction
Hypertension is the most common non-communicable disease worldwide. Over a billion people between 30 and 79 years of age, accounting for ∼1/3 of the world’s population, live with hypertension, the majority in lower- and lower-middle-income countries (LICs and LMICs). Almost half of the individuals with hypertension are unaware that they have hypertension. Fifty percent of those with a diagnosis receive treatment, out of whom only one-fifths have their blood pressure (BP) under control.S1 A recent study from India showed that only 8.5% of people living with hypertension had controlled BP.1 Hypertension is the most important risk factor for cardiovascular and premature deaths (responsible for 12.8% deaths globallyS2 making it imperative to control BP in all individuals. This review examines the factors responsible for resistance to anti-hypertensive therapies and the strategies to improve BP control in people with treatment-resistant hypertension (TRH). PubMed/MEDLINE database was searched for articles relevant to TRH and references were hand-picked to answer the questions on prevalence, outcomes, pathophysiology, causes, and therapeutic strategies, including newer drugs and device treatments. In this in-depth review, we discuss salient points in evaluation and provide clinical practice guidance for the management of TRH.
Definition of TRH
TRH is defined when BP is uncontrolled despite the use of maximum tolerated doses of at least three antihypertensive agents, including a diuretic; or when four or more antihypertensives are needed to achieve target BPs (controlled TRH) after assuring medication compliance and excluding the white coat effect [Figure 1].2
Prevalence of TRH
Population-based and clinic-based studies show a prevalence of TRH of 5-30%.S3-S7 Two observational studies report a prevalence of 11% and 19% in India.S8,S9 The prevalence is higher (>20%) when patients with secondary hypertension, especially chronic kidney disease (CKD), are included.S10 Higher prevalence (∼35%) in clinical trials is often attributed to selection bias and indications for patient enrolment (patients at risk of adverse outcomes), and forced titration that unmasks TRH by reducing suboptimal treatment.3 The prevalence of true TRH is probably between 5-10%.4
Impact of TRH
People with TRH have poor clinical outcomes. They have a 50% higher risk of cardiovascular events, kidney failure, and mortality compared with those with controlled BP.S11 There is a lack of longitudinal outcome data of TRH from India. The high risk of major adverse cardiovascular events is often driven by the development of CKD.S3 TRH also increases the risk of development of CKD.S11 Patients with CKD and TRH tend to do worse than those whose BP is controlled.5 A similar adverse prognostic impact of TRH has also been noted in patients with ischemic heart disease. Though BP control should be the goal in all patients with TRH, the long-term benefit may not be as substantial as in patients with controlled hypertension (13% risk reduction in heart failure, stroke, and coronary artery disease in TRH vs. 31% in those without TRH).6 Therefore, TRH represents an important public health problem.
Characteristics of people with TRH
Men, people of older age, and those of the black race have a higher burden of TRH.7 Further, people with certain co-morbidities like obesity, diabetes mellitus, higher Framingham 10-year risk score, albuminuria, left ventricular hypertrophy, obstructive sleep apnea (OSA), and other sleep disturbances are more prone to develop TRH.7-12 Vascular disease (atherosclerosis, impaired endothelial function, reduced arterial compliance, and raised systemic vascular resistance) has been demonstrated to be more pronounced in TRH than in controlled hypertension. Attenuation of nocturnal dipping in BP or reverse dipping, known to be associated with increased cardiovascular risk, is commonly observed in TRH cohorts, with a high proportion of patients having impaired renal function at baseline.S12 Metabolic derangements, such as hyperuricemia, aldosterone excess, suppressed plasma renin activity, and salt sensitivity, have also been observed more frequently in TRH.S12-S15 Clinical phenotypes in TRH are related to the underlying predominant pathophysiology: aldosterone-related, volume-dependent, sympathetic overactivity-driven, vascular pathology-related, and, more recently, phenotypes dictated by underlying pharmacogenomics. These phenotypes are often interrelated, yet knowing the signatures in a given patient can help tailor therapy to improve outcomes rather than following a ‘one-size-fits-all’ protocolized approach.S15
Diagnostic caveats in TRH
Factors leading to apparent resistance to antihypertensive treatment need to be ruled out before diagnosing TRH. Standardized BP measurement is lower than routine office BP by 14 mmHg.13 The white-coat effect may be seen in approximately 50% of hypertensives, with a mean difference of 18/6 mmHg between clinic and ambulatory BP in one study.14
Non-adherence, defined as ‘not taking medication as prescribed by a healthcare professional’, is common in many chronic conditions, including hypertension. It can be intentional or unintentional, the latter, sometimes, being related to multiple antihypertensive drug intolerance. Research suggests that nearly 50% people with apparent TRH are either completely or partially nonadherent to medication. Younger age, female sex, pill burden, and certain drugs (diuretics and calcium channel blockers) are associated with nonadherence.S16-S18
The other important medication-related factors to consider are clinical or physician inertia (inappropriately titrating medication), the use of non-rational antihypertensive drug combinations, and the use of certain concomitant medications.4 The commonly used drugs that can potentially reduce the efficacy of antihypertensive therapy are nonsteroidal anti-inflammatory agents, oral contraceptives, hormone replacement, sympathomimetics, liquorice, and certain recreational drugs.S19 In nephrology practice, one should also consider erythropoiesis-stimulating agents and immunosuppressants like cyclosporin.S20,S21 With the rising prevalence of obesity across the world, obesity with or without obstructive sleep apnea is a common reason for apparent treatment resistance.15,16 Sympathetic overactivity and activation of the renin-angiotensin-aldosterone system are implicated.17 Another patient-related factor is high dietary salt intake, which is more common in certain populations, including South Asians.18
Investigations
The investigations for TRH are mainly targeted at identifying apparent treatment resistance and excluding secondary forms of hypertension. Ambulatory blood pressure monitoring is the gold standard for ruling out white-coat effect. However, it may not always be available, especially in resource-limited settings. Furthermore, many people find 24-h BP monitoring uncomfortable, cumbersome, and even painful. In these circumstances, home BP monitoring should be carried out over 3 to 7 days, taking at least two readings in the morning and two in the evening, following standardized BP measurement guidance.19
Assessment of treatment adherence is the second most important step. No single method has been found completely foolproof. Indirect methods of assessment include pill counts, clinic interviews, and adherence assessment tools or questionnaires. Direct methods include witnessed drug intake, pharmacy database studies, medication event monitoring systems, measurement of pharmacodynamic parameters, and drug monitoring in body fluids. A combination of approaches is more likely to be successful.20 In resource-rich settings, liquid chromatography mass spectrometry (LC-MS) based urine assays have been used in recent years. It is a simple test that can identify the presence of multiple drugs, both antihypertensives and others (including antidiabetic and cardiovascular protective agents), from a single, small sample of urine. However, it identifies only cross-sectional nonadherence, rather than long-term.21,22
CKD is the commonest cause of secondary hypertension. The CRIC study showed that every 5 mL/min/1.73 m2 decrease in eGFR confers a 14% increase in risk of TRH.5 Doubling of proteinuria also increases the risk. In the ALLHAT trial, serum creatinine >1.5mg/dL strongly predicted failure to achieve BP target.23 Impaired sodium excretion (by reducing the effectiveness of diuretics and blunting vascular response to anti-hypertensives), activated RAAS, underlying intrinsic glomerular disease, premature vascular ageing, increased sympathetic nervous tone, reduced baroreceptor sensitivity in CKD contribute to TRH in the presence of kidney disease,S10,S22 Those with abnormal urinalysis and/or raised serum creatinine need to have a full work-up, including an ultrasound of the kidneys. Renal artery imaging (either CT or MR angiography) is required to rule out critical stenosis of renal arteries, either due to fibromuscular dysplasia, atherosclerosis, or other causes.
To rule out endocrine causes of hypertension, the measurement of serum renin: aldosterone, 24-h urine cortisol, and plasma or urine catecholamines and metanephrines is necessary to screen for Conn’s syndrome, Cushing’s syndrome, and pheochromocytoma. Approximately 20% of patients with TRH can have primary aldosteronism (PA).S23 Diagnosis requires confirmatory testing in those who screen positive by the most widely accepted screening test- aldosterone renin ratio (ARR).S24 Screening for other endocrine causes of hypertension is necessary, especially when the work-up for primary aldosteronism is negative.S25 Cushing’s syndrome, though typically manifests with hypertension, is not commonly associated with TRH. Hypo- or hyper-thyroidism, congenital adrenal hyperplasia, mineralocorticoid excess, acromegaly, and hyperparathyroidism are also less frequent causes of secondary endocrine hypertension.
Further evaluation should focus on ruling out treatable causes of hypertension, like sleep disorders and obstructive sleep apnea, the latter may be present in as high as 70-90% of patients, rooted in aldosterone excess, increased fluid retention, and accompanying upper airway oedema. Screening by overnight oximetry alongside the use of a sleep questionnaire (e.g., Epworth Sleepiness Scale) is the first step, followed by polysomnography to confirm OSA. One should also consider 24-h urine sodium measurement to rule out excessive salt intake as the cause of treatment resistance.
Treatment of TRH
The therapeutic options for TRH are limited and can broadly be divided into non-pharmacological measures, additional medication usage, and device therapy [Figure 2].
Non-pharmacological measures
The importance of strict adherence to a healthy lifestyle should be emphasized to everyone with TRH, as this may improve BP control to an extent, even in the face of ineffectiveness of medications. Even a small improvement in BP control is associated with a significant reduction in the risk of cardiovascular events and mortality.24 The main elements of lifestyle advice are: to maintain normal weight for adults (BMI 20-25 kg/m2), to reduce salt intake <100 mmol/day (<6g NaCl/<2.4 g Na+/d), to limit alcohol consumption to <2 units/day, moderate intensity physical exercise ideally on most of days of week for at least 150 min/ week, to eat food rich in fresh fruit and vegetables and low in total and saturated fat (DASH/modified-DASH diet).25-27 Each element of lifestyle changes is known to lower BP by 3-5 mmHg.
Rationalizing drug treatment
The first step is to ensure that the patient is on the correct combination of antihypertensive agents, i.e., on the maximum tolerated doses of a RAAS blocker, a calcium channel blocker (usually a dihydropyridine agent), and a thiazide or a thiazide-like diuretic. Spironolactone, a mineralocorticoid inhibitor, is the most effective 4th-line agent.S26 However, a recent trial suggests amiloride, a potassium-sparing diuretic, is as effective as spironolactone in TRH.28 Further drug therapy may include an alpha-blocker, a beta-blocker, or a vasodilator. However, the use of medications after the 5th agent generally provides marginal benefit in terms of BP control. Single-Pill Combination (SPC) therapy has been demonstrated to be more effective than using multiple single agents, probably because of improved adherence to treatment.29 Most guidelines recommend SPCs considering their cost-effectiveness, faster attainment of BP goals, and the potential to reduce cardiovascular risk.30,S6,S7
Device-based therapy
The contribution of increased efferent sympathetic activity to uncontrolled BP is significant. This involves stimulation of beta1-adrenergic receptors on juxtaglomerular cells, stimulating the release of renin and activation of the RAA system and downstream effects. Additionally, constriction of glomerular arterioles and central sympathetic signaling are other major effectors.S27 Hyperactivity of the sympathetic nervous system is strongly correlated with severe hypertension. Devices that attenuate sympathetic nervous system dysfunction are increasingly used to treat TRH [Figure 3]. One of the earliest procedures, lumbar sympathectomy, predates the discovery of many anti-hypertensive drugs, but was discarded due to severe impairment of essential sympathetic function (orthostatic hypertension, erectile dysfunction, bladder-bowel incontinence), and with the advent of effective antihypertensive medication. Sound physiological principles and surgical precedent underpinned the development of renal denervation as a therapy for treatment resistant hypertension.31
Renal denervation therapy
The initial enthusiasm for percutaneous, transcatheter renal sympathetic denervation following the first two uncontrolled SYMPLICITY-HTN trials was tempered after the demonstration of lack of efficacy in the sham-controlled SYMPLICITY-HTN3 trial.32-34 Concerns about potential confounding caused by incomplete denervation sparked interest in newer techniques for achieving more complete denervation. Radiofrequency ablation (Symplicity Spyral system, Medtronic), ultrasound ablation (Paradise system, Recor Medical), and alcohol injection (Peregrin system, Ablative Solutions) are techniques that have been studied.31
Symplicity SPYRAL systems targeting four quarters of the renal artery and its branch vessels were used for more complete denervation in the SPYRAL HTN OFF-MED and ON-MED trials. Both trials demonstrated the benefit of renal denervation compared with a sham procedure.35,36 However, the next expanded study of SPYRAL HTN ON-MED did not meet the primary efficacy endpoint.S28 Paradise ultrasound-based system is designed to deliver two ultrasound waves of seven seconds each, in the main renal artery. The RADIANCE trials in mild to moderate hypertension (RADIANCE-HTN SOLO, RADIANCE II) and TRH (RADIANCE-HTN TRIO) demonstrated a favorable short-term effect of renal denervation; however, long-term efficacy remains to be seen.37-39
The REQUIRE RCT in Japanese and South Korean patients with resistant hypertension did not show any difference in BP control in renal denervation versus sham procedure groups.40 The difference was attributed to better BP control in the control arm. Netrod-HTN Trial, SMART OFF-MED Trial, and other trials are presently ongoing in this region. However, the field stands to benefit from implementational research for assessing the burden of resistant hypertension, patient phenotypes, standardization of procedure, cost, and long-term efficacy studies. Though the SPYRAL and Paradise systems have received FDA approval, no clinical predictors of response have been identified, efficacy in high-risk groups, including kidney disease and resistant hypertension, has not been demonstrated, long-term safety and efficacy have not been established, and most importantly, no hard outcome data are available.S29 Despite this, many international guidelines recommend renal denervation for the treatment of TRH, as the current pharmacotherapy beyond the 4th or 5th line agent is largely ineffective in significantly reducing blood pressure in these patients.S30-S34
Baroreceptor activation therapy
Baroreceptors are stretch-sensitive fibers in the aortic arch and carotid bifurcation, which are triggered by vessel stretching. The afferent signals are transmitted to the nucleus tractus solitarii in the dorsal medulla, initiating a cycle of negative feedback to decrease the sympathetic tone and increase the parasympathetic tone.S35 Baroreflex activation therapy (BAT) is a method of transcutaneous stimulation of baroreceptors to lower the sympathetic tone, and is currently approved in Europe for TRH. The first system was tested in the DEBuT-HT trial in 2010, with a second-generation simplified system (Barostim Neo) later reproducing efficacy.S36,S37 A meta-analysis found that BAT resulted in significant reductions in SBP in both short- and long-term follow-up (-21 mmHg and -38 mmHg in 1-6 months and ≥12 months, respectively).41
MobiusHD, an implantable modulator that induces geometric changes of the carotid sinus, leading to enhanced baroreceptor sensitivity, was first tested in the European CALM-FIM study, where a mean reduction in office and 24-h ambulatory BP of 24/12 mmHg and 21/12 mmHg, respectively, was observed at 6 months, with an acceptable safety profile.S38 Long-term follow-up showed sustained with further reduction of office BP by 30/12 mmHg at 3 years.42 Though approved in Europe for TRH, the wider applicability of BAT is limited by therapeutic inertia, invasiveness of the procedure, procedural safety, need for antiplatelet agents, anticipation of adverse neurological and cardiovascular events, and unknown long-term profile.
The other experimental device-based treatments for TRH are the ROX arterio-venous coupler device, carotid body ablation, cardiac neuromodulation therapy, vagal nerve stimulation, and deep brain stimulation.43
Novel drugs
Novel pathways are increasingly being targeted in recent hypertension trials. Some of these new drugs have demonstrated effective blood pressure reduction in TRH [Figure 3]. Aprocicentan, the dual endothelin A and B inhibitor, was evaluated specifically for TRH in the PRECISION study, where a modest but statistically significant decrease in BP was observed. The least square mean changes in office systolic BP were -15.3 mmHg and -15.2 mmHg for aprocitentan 12.5 and 25 mg at 4 weeks, respectively, compared to -11.5 mmHg for placebo.44 Baxdrostat, a selective aldosterone synthase inhibitor, was found to reduce serum and urine levels of aldosterone by >50% in the BrigHTN trial.S39 The results of the phase 3 trial in uncontrolled and resistant hypertension show overwhelming benefit with the placebo-corrected difference of systolic BP -8.7 mmHg (95% CI, -11.5 to -5.8) with 1-mg baxdrostat and -9.8 mmHg (95% CI, -12.6 to -7.0) with 2 mg baxdrostat (p <0.001 for both comparisons).45 Lorundrostat, another aldosterone synthase inhibitor, showed efficacy in TRH in the Advance HTN trial, with the least-squares mean change in 24-h average systolic BP being -15.4 mmHg and -13.9 mmHg in the stable-dose group and dose-adjustment group, respectively, at 12 weeks, versus -7.4 mmHg with placebo.46 Zilebesiran (ligand-linked small interfering RNA) decreased serum angiotensinogen levels and caused sustained blood pressure reductions in patients with treated or untreated hypertension after a single subcutaneous dose in a phase 1 trial.47 These novel drugs raise optimism for future management of TRH. However, when marketed, the cost of these drugs might prohibit widespread use.
Digital health interventions
Digital interventions in hypertension include virtual communication, remote monitoring, smartphone-based applications, websites, Artificial Intelligence (AI), and Machine Learning (ML) to improve adherence and lifestyle, personalize treatment plans, and bring further innovations in clinical management.48 Some of these have been systematically shown to be cost-effective.S40
A 2023 meta-analysis, designed to answer the question of the efficacy of mHealth interventions in uncontrolled hypertension, included 13 RCTs and concluded that these interventions were more effective than usual care (57.5% vs. 40.8%) in controlling BP and reduced SBP and DBP by 4.45 mmHg and 2.47 mmHg, respectively.49 Another systematic review brought out the potential to improve patient engagement.S41 The European Society of Hypertension now endorses digital health and self-monitoring for control of hypertension.8,S6 Newer avenues such as Blockchain, a network-based, tamper-proof, public digital ledger for anonymized patient data, including that gathered from patients’ electronic data-capturing devices, are being explored in healthcare with the promise of improved data safety and stability, and recently as a platform for performing RCTs.S42 Artificial Intelligence (AI) and Machine Learning (ML) have the potential to overcome barriers in clinical practice, patient compliance, prognostication, and BP management.S43
Management of TRH in the South Asian population
South Asians (SAs) are disproportionately impacted by a greater risk of hypertension and premature, severe cardiovascular disease, due to unique metabolic, genotypic, phenotypic, and lifestyle characteristics.50 Estimates of the prevalence of TRH in this region range from 3.4-24%.S7, S8,S44-S46 Obesity (WHO recommended cut-off for definition in SAs: 25 kg/m2), age, high dietary salt intake, diabetes, and OSA are common risk factors recurrently identified across observational studies in the region.S7,S45,S46 Diagnostic services such as ABPM may not be available in resource-limited settings, delaying the identification of TRH. Apart from the cost of routine antihypertensives, the cost and availability of specialized diagnostic tests, specialist consultations (cardiology, endocrinology, nephrology), and newer therapies may also limit optimal management of TRH.
A primary care team [Table 1] can work towards correct and early identification of TRH and initiate focused lifestyle measures such as modifying dietary practices (salt intake <5 gm/day, improving fruit and vegetable intake, substituting millets for rice), cutting down on alcohol and smoking, incorporating physical exercise, yoga, maintaining BMI <23.5 kg/m2, discouraging herbal remedies or over-the-counter analgesics, and prescribing low cost or generic pills or SPCs to improve compliance. Secondary and tertiary care networks can focus on specialized hypertension services by filling resource and expertise gaps across the region. Actionable adaptations of existing guidelines and observational data can lead to meaningful progress in care delivery across all tiers of healthcare [Figure 4]. Spironolactone can serve as an efficacious and affordable alternative to newer MRAs. Substituting HBPM for ABPM, improving availability of screening tests for secondary causes, early risk stratification using suitable calculators (QRISK2 score, WHO/ISH-CVD score), and utilizing teleconsultations and digital health tools for follow-up can improve long-term outcomes. Developing tertiary care services and fostering research can ensure contemporary delivery of global developments to patients with TRH.
| Healthcare network tiers | Medical and paramedical personnel available | Diagnostic and therapeutic facilities available for TRH | Specific goals | Common goals |
|---|---|---|---|---|
| Tertiary care network | Hypertension specialist |
Rationalizing drug therapy Risk stratification Ordering specialized tests- ABPM, 24-h urinary Na/K, CT/MRI angiography, AVS Integration with other specialists |
Achievement of targets for BP controls in patients with TRH utilizing all resources |
Logistics of care delivery Quality of care audits Clinical trials and research Registry and long-term outcome studies Interaction with primary and secondary care providers regarding the patient’s progress Function as a tertiary node for telemedicine Encourage regional, national, and international collaboration in respective specialty Policy making and implementation |
| Cardiologist |
Risk stratification and optimization Renal denervation |
Improve CV outcomes in TRH | ||
| Nephrologist | Diagnosis and management of CKD | Identify and address the contribution/causality of kidney diseases in TRH | ||
| Endocrinologist |
Diabetes therapy Medical management of obesity Aldosterone axis evaluation Other endocrine evaluations |
Identify and address the contribution/causality of kidney diseases in TRH | ||
| Surgical and intervention specialists |
Device therapy Renal denervation Adrenal and endocrine surgeries Bariatric surgery |
Address surgically curable causes of TRH Implement approved device therapies for TRH |
||
| Sleep physician |
Polysomnography CPAP therapy |
Management of OSA and sleep disorders in TRH | ||
| Pharmacist |
Chemical testing for adherence Pharmacovigilance ADR monitoring |
Mitigate adverse outcomes from medication usage and related issues | ||
| Dietician | Diet counselling and follow-up | Mitigate adverse outcomes of improper dietary practices in TRH | ||
| Psychiatric services |
Stress management Deaddiction CBT for improving adherence to therapy |
Mitigate adverse outcomes of treatable psychological conditions in TRH | ||
| Secondary care network | Physician (involved in the practice of hypertension) |
Confirm diagnosis of TRH- by ABPM Reinforce lifestyle measures Addition of 4th agent Diagnose common secondary causes of TRH |
Confirm diagnosis of TRH Rationalize the therapy of TRH Rule out secondary causes of TRH |
Rationalizing drug therapy Risk stratification Offer primary screening for secondary causes |
| Cardiologist |
Risk stratification and management Assess feasibility for device therapy |
|||
| Nephrologist | Kidney disease screening and management | |||
| Endocrinologist |
Diabetes and weight management Aldosterone axis and other endocrine disorder screening |
|||
| Dietician | Diet counselling and follow-up | Mitigate adverse outcomes of improper dietary practices in TRH | ||
| Primary care network | Primary care physician or family physician |
Rule out apparent TRH (non-compliance, white coat effect, confounders) Reinforce compliance and lifestyle measures Encourage HBPM Periodic patient follow-up Coordination with higher centers |
Identify TRH and initiate primary treatment (4th line agent) Initiate timely referrals for patients with TRH Engage in a long-term course of patient |
Identify and initiate primary care in TRH cases Knowledge, attitude, and practice improvement regarding TRH in the community |
| Primary care nurse/Community health worker |
Standardized BP measurements Diet/exercise counselling Home visits Community awareness programs Peer support groups First tier of digital health interventions |
Generate awareness, impart education about hypertension and TRH in patients and the community Active participation in care delivery |
||
| Pharmacist |
Maintenance of community pharmacy Procurement of generic medicines and SPCs ADR reporting |
Prevent adverse outcomes in TRH due to unavailability or improper usage of antihypertensive agents |
ADR: Adverse drug reaction, ABPM: Ambulatory blood pressure monitoring, AVS: Adrenal vein sampling, BP: Blood pressure, CKD: Chronic kidney disease, CPAP: Continuous positive alveolar pressure, CT: Computed tomography, CV: Cardio-vascular, MRI: Magnetic resonance imaging, SPC: Single pill combination, TRH: Treatment resistant hypertension
Although true TRH is prevalent in 5-10% of the hypertensive population, its implications at both individual and population levels are enormous. Therapeutic options in TRH are limited; lifestyle modification, rationalizing antihypertensive drug combinations, and addition of further medication are the mainstay of current management. Device therapy, in particular renal sympathetic denervation, and newer antihypertensive agents, aldosterone synthetase inhibitors, endothelin receptor blockers, and small interfering RNA therapy, show promise. Further studies are needed to identify pathophysiological factors responsible for the resistance to antihypertensive treatment that may help to develop targeted therapies in the future.
Author contributions
Conceptualization, study design and methods development: UA, ID; Data collection, data analysis, writing (original draft): UA, ST, ID; Writing (critical revision and editing): ST, UA, ID; Supervision, Project administration: UA, ID. All authors provided final approval to the work.
Conflicts of interest
There are no conflicts of interest.
The authors declare that no generative AI or AI-assisted tools were used in drafting, editing, or preparing this manuscript.
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