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MY APPROACH
Year : 2015  |  Volume : 1  |  Issue : 1  |  Page : 60-64

An approach to diagnosis and management of resistant hypertension


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 Publication22-May-2015

Correspondence Address:
Dr. Ranil de Silva
Royal Brompton Hospital, London SW3 6NP
United Kingdom
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2395-5414.157574

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  Abstract 

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 Top


Hypertension is a key determinant of cardiovascular disease morbidity and mortality, directly accounting for approximately 10% of deaths in India. [1] In urban India, the reported prevalence of hypertension ranges between 20% and 33% and of concern this figure is increasing. [2] 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. [3] 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. [2] 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. [4] This review summarizes a management approach in patients with resistant hypertension, focusing on accurate diagnosis and evidence-based treatments.


  Definition Top


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. [5] The diagnosis is only confirmed after pseudo-resistant and secondary hypertension have been excluded.


  Pseudo-resistant Hypertension Top


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. [6]

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. [7] Importantly, patients with white-coat hypertension experience fewer cardiovascular complications than those with true resistant hypertension. The Indian Guidelines on Hypertension [8] along with other international guidelines recommend the use of ambulatory monitoring or home monitoring in apparent drug resistant hypertension. [5],[9],[10] 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. [11] 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. [12] 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. [13] 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 Top


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]. [6] It is important to screen resistant hypertension patients to exclude secondary causes, as specific interventions are usually indicated.
Table 2: Secondary causes in patients with resistant hypertension


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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.
Table 3: Substances that may elevate BP


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  Management of Resistant Hypertension Top


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 Top


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. [4],[9],[14] 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. [15]


  Drugs Top


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. [5] 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. [16] 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. [6]

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. [17] 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). [18]


  Upcoming Treatments Top


Surprisingly, there are <10, randomized, blinded, placebo/sham-controlled clinical trials that specifically investigate the resistant hypertension population. [19] 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), [20] 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. [21] 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). [19],[22] 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, [23] and the creation of an arteriovenous anastomosis using a ROX coupler that is implanted between the iliac artery and vein using an endovascular approach. [24] 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. [25]


  Summary Top


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.

 
  References Top

1.
Patel V, Chatterji S, Chisholm D, Ebrahim S, Gopalakrishna G, Mathers C, et al. Chronic diseases and injuries in India. Lancet 2011;377:413-28.  Back to cited text no. 1
    
2.
Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: Analysis of worldwide data. Lancet 2005;365:217-23.  Back to cited text no. 2
    
3.
Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 62 prospective studies. Lancet 2002;360:1903-13.  Back to cited text no. 3
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4.
Patel H, di Mario C. Renal denervation for hypertension: Where are we now? Br J Cardiol 2013;20:142-7.  Back to cited text no. 4
    
5.
National Institute for Health and Care Excellence. Hypertension: Clinical Management of Primary Hypertension in Adults. CG 127, August 2011. Available from: http://www.nice.org.uk/guidance/cg127. [Last accessed on 2015 Apr 14].  Back to cited text no. 5
    
6.
Myat A, Redwood SR, Qureshi AC, Spertus JA, Williams B. Resistant hypertension. BMJ 2012;345:e7473.  Back to cited text no. 6
    
7.
de la Sierra A, Segura J, Banegas JR, Gorostidi M, de la Cruz JJ, Armario P, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension 2011;57:898-902.  Back to cited text no. 7
    
8.
Association of Physicians of India. Special Issue on Indian Guidelines on Hypertension (IGH)-III. J Assoc Physicians India 2013;61:6-61.  Back to cited text no. 8
    
9.
JBS Board. Joint British Societies′ consensus recommendations for the prevention of cardiovascular disease (JBS3). Heart 2014;100 Suppl 2:ii1-67.  Back to cited text no. 9
    
10.
Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension: diagnosis, evaluation, and treatment: A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation 2008;117:e510-26.  Back to cited text no. 10
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11.
O′Brien E, Asmar R, Beilin L, Imai Y, Mallion JM, Mancia G, et al. European Society of Hypertension recommendations for conventional, ambulatory and home blood pressure measurement. J Hypertens 2003;21:821-48.  Back to cited text no. 11
    
12.
Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: Longitudinal study of electronically compiled dosing histories. BMJ 2008;336:1114-7.  Back to cited text no. 12
    
13.
Bunker J, Callister W, Chang CL, Sever PS. How common is true resistant hypertension? J Hum Hypertens 2011;25:137-40.  Back to cited text no. 13
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14.
Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012;33:1635-701.  Back to cited text no. 14
    
15.
Pimenta E, Gaddam KK, Oparil S, Aban I, Husain S, Dell′Italia LJ, et al. Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension: Results from a randomized trial. Hypertension 2009;54:475-81.  Back to cited text no. 15
    
16.
Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA 2000;283:1967-75.  Back to cited text no. 16
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17.
The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-59.  Back to cited text no. 17
    
18.
Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367:2204-13.  Back to cited text no. 18
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19.
Patel HC, Hayward C, Ozdemir BA, Rosen SD, Krum H, Lyon AR, et al. Magnitude of blood pressure reduction in the placebo arms of modern hypertension trials: Implications for trials of renal denervation. Hypertension 2015;65:401-6.  Back to cited text no. 19
    
20.
Symplicity HTN-2 Investigators, Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial. Lancet 2010;376:1903-9.  Back to cited text no. 20
    
21.
Bhatt DL, Kandzari DE, O′Neill WW, D′Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393-401.  Back to cited text no. 21
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22.
Patel HC, Hayward C, Di Mario C. SYMPLICITY HTN 3: The death knell for renal denervation in hypertension? Glob Cardiol Sci Pract 2014;2014:94-8.  Back to cited text no. 22
    
23.
Bisognano JD, Bakris G, Nadim MK, Sanchez L, Kroon AA, Schafer J, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: Results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol 2011;58:765-73.  Back to cited text no. 23
    
24.
Lobo MD, Sobotka PA, Stanton A, Cockcroft JR, Sulke N, Dolan E, et al. Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): A randomised controlled trial. Lancet 2015;385:1634-41.  Back to cited text no. 24
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25.
Patel HC, Rosen SD, Lindsay A, Hayward C, Lyon AR, di Mario C. Targeting the autonomic nervous system: Measuring autonomic function and novel devices for heart failure management. Int J Cardiol 2013;170:107-17.  Back to cited text no. 25
    


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  In this article
   Abstract
  Introduction
  Definition
   Pseudo-resistant...
   Secondary Hypert...
   Management of Re...
  Lifestyle
  Drugs
  Upcoming Treatments
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