|Year : 2015 | Volume
| Issue : 1 | Page : 60-64
An approach to diagnosis and management of resistant hypertension
Hitesh C Patel1, Carl Hayward1, Ranil de Silva2
1 NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London; National Heart and Lung Institute, Imperial College, London, United Kingdom
2 NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London; National Heart and Lung Institute, Imperial College, London; Department of Cardiology, Ealing Hospital, Southall, United Kingdom
|Date of Web Publication||22-May-2015|
Dr. Ranil de Silva
Royal Brompton Hospital, London SW3 6NP
Source of Support: None, Conflict of Interest: None
Hypertension is a key determinant of cardiovascular disease morbidity and mortality, directly accounting for approximately 10% of deaths in India. There is a causal association between the magnitude of blood pressure (BP) elevation and adverse cardiovascular event rate, which provides the rationale for implementing BP reduction in routine clinical practice. However, an estimated 30-50% of the hypertensive population remain uncontrolled with a BP >140/90 mmHg, of whom a subgroup fulfill the diagnostic criteria for resistant hypertension. This cohort lies at the extreme end of the cardiovascular risk spectrum, and hence stands to benefit most from specialist input to optimize BP control. This review summarizes a management approach in patients with resistant hypertension, focusing on accurate diagnosis and evidence-based treatments.
Keywords: Arterio-venous coupler, renal denervation, resistant hypertension, pseudo-resistant hypertension, secondary hypertension
|How to cite this article:|
Patel HC, Hayward C, de Silva R. An approach to diagnosis and management of resistant hypertension. J Pract Cardiovasc Sci 2015;1:60-4
|How to cite this URL:|
Patel HC, Hayward C, de Silva R. An approach to diagnosis and management of resistant hypertension. J Pract Cardiovasc Sci [serial online] 2015 [cited 2021 Jun 18];1:60-4. Available from: https://www.j-pcs.org/text.asp?2015/1/1/60/157574
| Introduction|| |
Hypertension is a key determinant of cardiovascular disease morbidity and mortality, directly accounting for approximately 10% of deaths in India.  In urban India, the reported prevalence of hypertension ranges between 20% and 33% and of concern this figure is increasing.  There is a causal association between the magnitude of blood pressure (BP) elevation and adverse cardiovascular event rate, which provides the rationale for implementing BP reduction in routine clinical practice.  However, an estimated 30-50% of the hypertensive population remain uncontrolled with a BP > 140/90 mmHg, of whom a subgroup fulfill the diagnostic criteria for resistant hypertension.  This cohort lies at the extreme end of the cardiovascular risk spectrum, and hence stands to benefit most from specialist input to optimize BP control.  This review summarizes a management approach in patients with resistant hypertension, focusing on accurate diagnosis and evidence-based treatments.
| Definition|| |
Resistant hypertension is defined when seated BP readings exceed 140/90 mmHg despite treatment with at least three first-line antihypertensive agents at maximally tolerated doses, one of which should be a diuretic.  The diagnosis is only confirmed after pseudo-resistant and secondary hypertension have been excluded.
| Pseudo-resistant Hypertension|| |
Many patients with elevated BP readings are incorrectly diagnosed with resistant hypertension and are considered as having pseudo-resistant hypertension. The three commonest causes include: white coat hypertension, poor medication adherence, and incorrect BP measurement. 
White coat hypertension, which is also termed isolated office hypertension, refers to elevated BP measurements in the clinic but normal readings at home [Figure 1]. Up to one-third of patients with apparent resistant hypertension may be reclassified as white coat after ambulatory BP monitoring.  Importantly, patients with white-coat hypertension experience fewer cardiovascular complications than those with true resistant hypertension. The Indian Guidelines on Hypertension  along with other international guidelines recommend the use of ambulatory monitoring or home monitoring in apparent drug resistant hypertension. ,, Those patients who are able to perform home monitoring should be advised to purchase validated upper arm monitors only (www.dableducational.org) with costs starting at Rs. 1099. Patients should be encouraged to record in a diary two measurements, 3 min apart in the morning (0600-0900) and two in the evening (1800-2100) for 7 days. The readings from the 1 st day should be excluded as they represent a period of familiarization and an average of the subsequent 12 readings across 6 days recorded.  The numerical BP cut-off vary according to mode of measurement and are summarized in [Table 1].
|Figure 1: Flow chart summarizing the diagnosis and management algorithm in patients with resistant hypertension.|
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|Table 1: BP thresholds for the diagnosis of hypertension with different types of measurement|
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Poor compliance with medication is a common challenge when managing patients with any chronic illness and must be actively evaluated. In phase IV clinical studies, approximately 50% of patients had discontinued their anti-hypertensives by 1 year.  Reasons for discontinuation included side effects which reduce quality of life, cost, cognitive impairment and inadequate patient education. Where nonadherence is suspected, directly observed therapy if possible can be particularly helpful. In a study of 37 patients with apparent resistant hypertension, two-thirds achieved a systolic BP < 140 mmHg after supervised tablet administration.  It is difficult to test medication compliance objectively, but options include pill counting or urine/serum drug assays. The latter method will inform the clinician what medications were systemically active at the time of BP measurement rather than long term adherence. The management approach is dictated by identifying the causes for noncompliance but may include medication/dosage changes to mitigate side effects; use of fixed-dose combination drug tablets to reduce the number of ingested tablets; and use of prefilled pill boxes.
Measurement of BP is commonly performed incorrectly. It is important to first have the patient seated quietly for at least 5 min, before measuring BP, which should be repeated at least three times, allowing 2-3 min between each measurement. The cuff should be appropriate for the arm size. Using a disproportionately small cuff in a large arm will artificially overestimate BP. The brachial artery should be palpated during the first inflation to exclude an incompressible severely calcific artery as a cause of an elevated BP reading.
| Secondary Hypertension|| |
Though secondary causes of hypertension are found in only 5% of all patients with hypertension, they are more prevalent in the cohort of patients with resistant hypertension [Table 2].  It is important to screen resistant hypertension patients to exclude secondary causes, as specific interventions are usually indicated.
Medications, supplements, and recreational drugs may also inadvertently increase BP. A summary of potentially causal agents is provided in [Table 3]. Where possible these should down-titrated or withdrawn.
| Management of Resistant Hypertension|| |
This involves education, lifestyle modification, drugs and device therapy though the last approach currently remains confined to clinical trials. Testing for end-organ damage (left ventricular function/hypertrophy, renal function, fundoscopy and atherosclerosis (using carotid ultrasound or calcium score on cardiac computed tomography) is important but beyond the scope of this brief review. Unfortunately, there is no ideal surrogate marker of long-term BP control (as glycated hemoglobin is to diabetes).
| Lifestyle|| |
Opportunities to educate patients regarding lifestyle and its impact on BP should be taken at every consultation. Salt restriction (<6 g/day), aerobic exercise (30 min/day), reduction of alcohol intake (<21 units/week in men and < 14units/week in women) and weight loss can reduce BP. ,, Of note, a small randomized crossover trial demonstrated that dietary sodium restriction was able to reduce office BP by 20/10 mmHg in patients with resistant hypertension. 
| Drugs|| |
The National Institute for Health and Care Excellence recommends that the diagnosis of resistant hypertension should be made only if patients are receiving at least three synergistic, first-line anti-hypertensive agents; that is, an angiotensin-converting enzyme (ACE)-inhibitor or angiotensin receptor blocker (ARB) with a calcium channel blocker and a thiazide-type diuretic.  Drug doses should be up-titrated to the target or maximal tolerated dose. The thiazide-type diuretics of choice are either chlorthalidone or indapamide due to superior efficacy. Thiazide-type diuretics are less efficacious in patients with renal dysfunction and may need to be substituted for a loop diuretic when the estimated glomerular filtration rate is <40 ml/min/1.73 m 2 .
The fourth line agent with the largest evidence base is spironolactone. It should be used cautiously in patients with renal dysfunction and in whom potassium concentrations are >4.5 mmol/L due to the risk of hyperkalemia. If gynecomastia develops in men, due to anti-androgen effects, replacement with either eplerenone or amiloride, is recommended, though both these are less potent anti-hypertensives. Some thiazide or loop diuretics are available in fixed doses with amiloride. If the baseline potassium is >4.5 mmol/L, doubling the dose of the existing diuretic is recommended instead.
The evidence base for fifth line therapy is weak. However, in the first instance the choice would be adrenoreceptor blockade. If the heart rate is <60/min, an α-blocker would be most appropriate, otherwise an α-and/or β-blocker could be administered. Vasodilatory β-blockers are preferred for BP control and include carvedilol, labetalol (combined α-and β-receptor blockade) and nebivolol (β-blocker with nitric oxide bioactivity). Doxazosin increased the risk of congestive heart failure admission in the ALLHAT trial and hence should be avoided in patients with known left ventricular dysfunction.  Finally central sympatholytics (e.g. clonidine, moxonidine, methyldopa) or vasodilators (e.g. hydralazine, minoxidil) can be considered but their use is associated with a higher incidence of side effects.
If patients require the prescription of more than 3 anti-hypertensives, it is advisable to use fixed-dose combination therapy to improve treatment adherence and to use at least one drug at night to optimize 24 h BP control. 
The combination of ACE inhibitors with ARBs is not recommended due to the increased risk of adverse events (renal dysfunction, hyperkalemia, and syncope) without an increase in benefit observed in the ONTARGET trial.  Similarly, it is not recommended to prescribe aliskiren to patients concurrently on an ACE inhibitor or ARB following the early termination of the ALTITUDE trial due to futility as well as safety concerns (renal dysfunction, hyperkalemia and stroke). 
| Upcoming Treatments|| |
Surprisingly, there are <10, randomized, blinded, placebo/sham-controlled clinical trials that specifically investigate the resistant hypertension population.  Currently, efforts are underway to redress this with both pharmacological and device-based treatments at various stages of investigation.
Three devices have to date been investigated in multicenter, prospective, randomized, controlled trials to lower BP in patients with resistant hypertension [Figure 2]. Renal sympathetic denervation, which is a percutaneous technique that seeks to interrupt the renal sympathetic nerves by performing radiofrequency ablation, has been most intensively investigated. Though the initial phase II trial showed impressive reductions in office BP (33/11 mmHg),  the recently reported single-blind randomized sham-controlled SYMPLICITY-HTN 3 trial of 535 patients was neutral, but as previously, did not highlight significant safety concerns.  Several potential explanations for this discrepancy have been debated and include patient selection, regression to the mean bias and suboptimal ablation technique (operator and/or device related). , Research is currently underway to provide answers to the plethora of unresolved issues relating to the potential role of this technology for treating refractory hypertension.
|Figure 2: Three devices currently being investigated in the management of resistant hypertension. (a): Renal denervation with the Symplicity catheter.(Source: http://www.medtronic.com/rdn/mediakit/RDN%20Procedure%202%20-%20Catheter-based%20Energy%20Delivery.png). (b) Baroreceptor Activation Therapy (Source: http://www.cvrx.com/intl/patients-intl/hypertension/322-2/). (c) Arteriovenous coupler in the iliac vessels (Source: http://www.roxmedical.com/the-rox-solution/solution-overview/).|
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The other two devices are baroreflex activation therapy stimulation, which involves surgical implantation of a pacemaker-like device with a lead extending to the baroreceptors near the carotid artery,  and the creation of an arteriovenous anastomosis using a ROX coupler that is implanted between the iliac artery and vein using an endovascular approach.  Though the early data for these two products are promising, further data confirming safety and efficacy of these approaches in sham-controlled blinded randomized controlled trials are needed. Currently, none of the devices are recommended for the routine management of patients with resistant hypertension. 
| Summary|| |
A proposed algorithm to aid the clinician manage resistant hypertension is presented in [Figure 1]. Accurate diagnosis is fundamental. Excluding pseudo-resistance using ambulatory or home BP monitoring and evaluating treatment compliance is mandatory. Secondary causes of hypertension are common in the resistant cohort and should be actively sought. A patient-centered approach, which involves education and lifestyle modification, is required to develop a bespoke, well-tolerated and efficacious treatment regimen. Finally, those patients whose BP remains uncontrolled despite multiple pharmacologic agents, should be encouraged to enroll into clinical trials investigating novel therapies in resistant hypertension.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]