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Year : 2019  |  Volume : 5  |  Issue : 2  |  Page : 76-80

Pseudo-resistant, resistant, and refractory hypertension: The good, the bad, and the ugly

Department of Cardiology, All Institution of Medical Sciences, Rishikesh, Uttarakhand, India

Date of Submission02-May-2019
Date of Decision17-May-2019
Date of Acceptance28-May-2019
Date of Web Publication19-Aug-2019

Correspondence Address:
Dr. Dibbendhu Khanra
Department of Cardiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpcs.jpcs_31_19

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Resistant Hypertension (RH) not uncommon in daily clinical practice but is often loosely coined. Accuracy of BP measurement, Adherence to prescribed medications and Adequacy of prescribed dosages are to be ensured before diagnosing RH. Ambulatory blood pressure monitoring and home blood pressure monitoring are becoming standard of care in evaluation of RH patients. Management of RH in recent years has been evolved and spiranolactone has become the fourth drug when combination of Renin-Angiotensin system blockers, calcium channel blockers and long acting thiazide like diuretics fail. Scores like PFK comprising of Urinary pH>7, Female Sex, K<3.5 mg/dl has been handy in decision making to start spiranolactone. However, Refractory Hypertension (RfH) has been defined when five anti-hypertensive drugs including spiranolactone fail and has been emerging to be a novel phenotype. RH patients are known to be volume dependent whereas RfH patients are known to have sympathetic overdrive. Management strategy of RfH is challenging and beta-blockers or alpha-blockers may be of role in these subset. Renal artery denervation is being resurrected with newer evidence and definitely an option for RfH patients. Novel therapies like Barroreceptor Activation Techniques and Central iliac arteriovenous anastomosis are being evaluated in resistant and refractory hypertension patients.

Keywords: Ambulatory blood pressure monitoring, refractory hypertension, resistant hypertension

How to cite this article:
Khanra D, Duggal B. Pseudo-resistant, resistant, and refractory hypertension: The good, the bad, and the ugly. J Pract Cardiovasc Sci 2019;5:76-80

How to cite this URL:
Khanra D, Duggal B. Pseudo-resistant, resistant, and refractory hypertension: The good, the bad, and the ugly. J Pract Cardiovasc Sci [serial online] 2019 [cited 2023 Jun 4];5:76-80. Available from: https://www.j-pcs.org/text.asp?2019/5/2/76/264627

  Introduction Top

Hypertension (HTN) has reached a staggering figure all over the world, and one in three adults in India is hypertensive.[1] Resistant hypertension (RH) is defined as uncontrolled office blood pressure (BP) >130/80 mmHg despite three different groups of antihypertensive medications in optimum dose, including one of the long-acting diuretics.[2] Studies show that the prevalence of RH is 10% of total hypertensive patients.[3]

  What Are The Caveats Of Diagnosis Of Resistant Hypertension? Top

There are multiple caveats of diagnosis of RH.

  1. SPRINT trial showed that benefit of intensive lowering of BP, especially in aged hypertensives with higher cardiovascular risk,[4] has been the driving force behind the American heart Association/ American College of Cardiology (AHA/ACC) 2017 HTN guideline to set a lower target (<130/80 mmHg) to achieve.[5] Accordingly, the BP cutoff for diagnoses of RH has been changed from <140/90 mmHg to <130/80 mmHg in 2017 guideline
  2. Uncontrolled office BP has been used to define RH according to the 2018 European Society of Cardiology (ESC) guideline for HTN.[6] However, ambulatory BP monitoring (ABPM) has revolutionized the essence of BP lowering and stressed over 24-h control of BP including at nighttime. ABPM has identified four subsets of RH [Figure 1]. AHA/ACC and european society of cardiology (ESC) suggest that ABPM is mandatory before diagnosing RH to rule out white coat hypertension (WCH), which can be as high as 20% of the RH group, and also to follow-up the WCH patients.[6] Recently, there is growing evidence to support the use of home BP monitoring (HBPM)[7] for 6 times a day including nighttime BP and early morning BP, which has been shown to have good correlation with ABPM [Figure 2]
  3. National Institute for Health and Care Excellence (NICE) stressed upon using combination of angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, calcium channel blockers, and diuretic (A + C + D) including a long-acting thiazide. However, prescriptions of long-acting thiazides such as chlorthalidone or spironolactone have been found to be persistently low across the spectrum of RH.[8] A recent study has reiterated the role of chlorthalidone to reduce BP throughout the clock, whereas hydrochlorothiazide (HCTZ) has turned resistant hypertensive patients into masked HTN due to their short-acting property.[8] PATHWAY 3 has shown that a combination of amiloride with HCTZ was neutral for glucose and K+ and reduced BP more than each single diuretic.[9] Hence, in regard to a treatment RH, choosing the correct diuretic is of supreme importance.

  Secondary Hypertension Is Not As Same As Resistant Hypertension Top

All hypertensive patients at the time of diagnosis must have a thorough clinical history (for obstructive sleep apnea [OSA] and history suggestive of pheochromocytoma), clinical examinations (including peripheral pulses and abdominal mass), and echocardiography (to rule out coarctation of the aorta) and markers for connective tissue diseases (e.g., anti-nuclear antibody). [Figure 3] one of the most underrated causes of HTN is OSA, and sleep study may clinch the diagnosis for the suspected ones. Drugs such as nonsteroidal anti-inflammatory drugs and oral contraceptive pills and other hormonal therapies including steroids are also looked for while dealing with patients of RH.
Figure 1: Spectrum of resistant hypertension as per ambulatory blood pressure monitoring. RH: Resistant hypertension

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Figure 2: Normal and abnormal pattern of ambulatory blood pressure monitoring.

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Figure 3: Causes of secondary hypertension.

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Yamashita et al.[10] have developed PFK score which consists of U pH >7, female sex, K <3.5, primary hyperaldosteronism can be suspected if PFK scores are positive. Prescribing spironolactone ahs been found to be useful in controlling hypertension in this subset.

It has been found that plasma renin is low across the spectrum of RH, and PATHWAY 2 study demonstrated that spironolactone was the most effective BP -lowering agent throughout the distribution of baseline plasma renin, but it was particularly effective in patients with lower rennin.[11] However, changing antihypertensive medications according to plasma rennin to plasma aldosterone ratio was intuitively appealing but practically not feasible in most instances owing to poor availability, standardization, and hyporeninemic hypoaldosteronism in diabetes mellitus.

  How To Approach Management Resistant Hypertension? Top

Studies have shown that 50% of the total RH patients are actually having pseudo-RH and the rest 50% have true RH (TRH), and it can be due to white coat effect, inaccurate BP measurement, undertreatment, or medical nonadherence.[12] Hence, whenever office BP is >140/90 with A + C + D regimen, ABPM should be advised to rule out WCH and diuretics should be changed to long-acting chlorthalidone. Accuracy of BP measurement, adherence to prescribed medications, and adequacy of prescribed dosages are to be ensured (Triple-A).

According to the NICE guideline, in RH patients, after A + C + D regimen, the fourth drug to be decided as per the serum potassium (k) level. If k <4.5, a spironolactone has to be added, whereas if k >4.5, either double the dose of thiazide or adding a loop diuretic has been advised.[13]

  Can We Identify the True Resistant Hypertension and Masked Resistant Hypertension at the Clinic? Top

In a large community-based study of 8295 patients with RH classified on the basis of ABPM, de la Sierra et al.[14] found that true resistant hypertension patients who had longer duration of uncontrolled hypertension and needed four or more drugs to control BP, had a worse cardiovascular outcome. The group included larger proportions of smokers, diabetics, target organ damage (including left ventricular hypertrophy, impaired renal function, and microalbuminuria), and documented cardiovascular disease. Moreover, true resistant hypertensives exhibited in a greater proportion of a riser pattern in ABPM.

In J-HOME study[15] profiling of 3400 Japanese patients with RH by HBPM, it has been found that compared to controlled HTN, factors associated with isolated uncontrolled home HTN included obesity, relatively higher office systolic BP (SBP), habitual drinking, and the use of two or more prescribed antihypertensive drugs. Compared to uncontrolled HTN, factors associated with isolated uncontrolled office HTN included female gender, lower body mass index, and relatively lower office SBP. The presence of hypercholesterolemia was found to have a significant and independent association with isolated office RH. Higher office SBP, past history of ischemic heart disease, and lower prescription rate of potassium-sparing diuretics were found to have a significant and independent association with isolated home RH. Patients with sustained RH had a significantly lower prescription rate of potassium-sparing diuretics than those with controlled HTN.

  What Is “Refractory Hypertension:” Is It A Novel Phenotype? Top

One subset of TRH patients are not amenable to achievement of target BP despite using five different classes of antihypertensive drugs, including a long-acting thiazide lke diuretic and spironolactone. Acelajado et al. have coined them to have 'refractory hypertension (RfH).[16] They have found that 10% of the truly RH patients are RfH and they have a dismal outcome in terms of stroke and heart failure in comparison to TRH. Dudenbostel et al. defined RfH as failure to achieve BP control with treatment prescribed by HTN experts at a minimum of three follow-up visits during at least 6 months of care, receiving five or more different antihypertensive medications, including chlorthalidone and spironolactone. This stricter definition led the researchers to have a prevalence of RfH as 4% in their prospective study comprising 700 patients of TRH.[17]

Birmingham Hypertension Clinic at the University of Alabama at has proposed a classification of HTN according to number of drugs [Figure 4].[17] Dudenbostel et al. compared the profile of RfH to TRH patients and found that RfH patients are younger with low renin and high sympathetic activity [Figure 5].[17]
Figure 4: Classification of hypertension according to number of drugs.

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Figure 5: Comparison of true resistant hypertension and refractory hypertension.

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[Figure 6] summarizes the approach to RH.
Figure 6: Approach to resistant hypertension.

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  What Can Be The Last Resort For Refractory Hypertension Patients? Top

For the subset of RfH patients, transcatheter renal artery denervation (RDN) has been studied. However, the surge of initial enthusiasm was refuted in SIMPLICITY 3 study, where RDN was not found to be superior to a sham procedure and medical therapy in reducing office and ambulatory BP at 6 months. However, RDN has been found to have greater benefit in RfH patients with high mean BP (>199 mmHg), age <65 years, and estimated glomerular filtration rate >60 ml/min/m2.[18] However, recent studies such as RADIANCE-HTN SOLO and REQUIRED and SPYRAL HTN-ON MED and OFF MED showed the promising result of RDN, and the practice is rejuvenated with availability newer SPYRAL catheter by Medtronic.[19],[20]

Baroreceptor activation technique has been also studied in RfH patients. Initial phase III Rheos Pivotal Trial on continuous carotid baroreceptor pacing with RHEOS device for RH with the first-generation baroreceptor pacemaker yielded equivocal data on efficacy and adverse effects due to facial nerve injury during surgical implantation.[21]

Creation of a central iliac arteriovenous anastomosis (cAV) using a novel nitinol coupler device (ROX device) results in an immediate, significant reduction of BP. In ROX CONTROL HTN study, extended follow-up of patients with uncontrolled HTN treated with an iliac cAV anastomosis has demonstrated durable office and ABP reduction with no newly identified safety reports. The magnitude of office BP reduction that was observed at 6-month follow-up was greater than that reported after the use of renal denervation in TRH and also the use of spironolactone as a fourth-line antihypertensive drug strategy for TRH. However, after coupler therapy, one-third of patients developed ipsilateral venous stenosis; all were treated successfully with venous stenting.[22]

  Indian Scenario Top

In a study by Bharatia et al.,[23] 19.5% of hypertensive patients were resistant to A + C + D combination. Eighty percent of them were aged in the range of 46–65 years and 67.2% of patients were male. A higher proportion of patients were residents of Andhra Pradesh (21.4% patients) and Maharashtra (19.3% patients) in the aforesaid study. In a study reported from Varanasi, the prevalence of HTN was found to be staggering 32.9%. Out of the total hypertensive patients, only 38.4% were aware of their HTN status; of those, 70.4% were seeking treatment and 66% had their BP above target.[24] In a study by Roy et al., it has been found that the prevalence of HTN increased from 23.0% to 42.2% and 11.2% to 28.9% in urban and rural National Capital Region, respectively, over a span of two decades, irrespective of high education, alcohol use, obesity, and high fasting blood glucose being at a higher risk for HTN. Moreover, surprisingly, the study showed that, overall, there was no improvement in awareness, treatment, and control rates of HTN in the population.[25] In a meta-analysis by Anchala et al., about 33% of urban and 25% of rural Indians were found to be hypertensive. Of these, 25% of rural and 42% of urban Indians were aware of their hypertensive status. Only 25% of rural and 38% of urban Indians were being treated for HTN. Only one-tenth of rural and one-fifth of urban Indian hypertensive population had their BP under control.[1] However, data on RH in India are limited, and Narang and Srikant have elucidated the nuances in the application of 2017 HTN guidelines for Indian patients in their article.[26]

  Conclusion Top

The actual prevalence of RH may be lower than what is perceived in the literature when triple-A (accuracy of BP measurement, adherence of medications, and adequacy of anti-HTN medications) are ensured. It is important to emphasize that the sea of RH starts when the shore of secondary HTN is over and the island of RfH is still uncharted. RfH is emerging as a novel phenotype, and growing evidence suggest that these patients have sympathetic hyperactivity. However, the role of beta-blockers and interventions such as RDN and baroreceptor activation techniques is yet to be studied.

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Ethical clearance taken.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Anchala R, Kannuri NK, Pant H, Khan H, Franco OH, Di Angelantonio E, et al. Hypertension in India: A systematic review and meta-analysis of prevalence, awareness, and control of hypertension. J Hypertens 2014;32:1170-7.  Back to cited text no. 1
2. Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults; 2017.  Back to cited text no. 2
Abdalla M. Ambulatory blood pressure monitoring: A complementary strategy for hypertension diagnosis and management in low-income and middle-income countries. Cardiol Clin 2017;35:117-24.  Back to cited text no. 3
Berlowitz DR, Foy CG, Kazis LE, Bolin LP, Conroy MB, Fitzpatrick P,et al. Effect of intensive blood-pressure treatment on patient-reported outcomes. N Engl J Med 2017;377:733-44.  Back to cited text no. 4
Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA, et al. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing committee to develop guidelines on the management of adults with congenital heart disease). Developed in collaboration with the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;52:e143-263.  Back to cited text no. 5
Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021-104.  Back to cited text no. 6
George J, MacDonald T. Home blood pressure monitoring. Eur Cardiol 2015;10:95-101.  Back to cited text no. 7
Pareek AK, Messerli FH, Chandurkar NB, Dharmadhikari SK, Godbole AV, Kshirsagar PP, et al. Efficacy of low-dose chlorthalidone and hydrochlorothiazide as assessed by 24-h ambulatory blood pressure monitoring. J Am Coll Cardiol 2016;67:379-89.  Back to cited text no. 8
Brown MJ, Williams B, Morant SV, Webb DJ, Caulfield MJ, Cruickshank JK, et al. Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): A parallel-group, double-blind randomised phase 4 trial. Lancet Diabetes Endocrinol 2016;4:136-47.  Back to cited text no. 9
Yamashita T, Shimizu S, Koyama M, Ohno K, Mita T, Tobisawa T, et al. Screening of primary aldosteronism by clinical features and daily laboratory tests: Combination of urine pH, sex, and serum K. J Hypertens 2018;36:326-34.  Back to cited text no. 10
Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G,et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): A randomised, double-blind, crossover trial. Lancet 2015;386:2059-68.  Back to cited text no. 11
Bhatt H, Siddiqui M, Judd E, Oparil S, Calhoun D. Prevalence of pseudoresistant hypertension due to inaccurate blood pressure measurement. J Am Soc Hypertens 2016;10:493-9.  Back to cited text no. 12
National Institute of Health and Care Excellence: Hypertension in adults: diagnosis and management (CG127). 2016.  Back to cited text no. 13
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. 14
Obara T, Ohkubo T, Asayama K, Metoki H, Inoue R, Kikuya M, et al. Home blood pressure measurements associated with better blood pressure control: The J-HOME study. J Hum Hypertens 2008;22:197-204.  Back to cited text no. 15
Acelajado MC, Pisoni R, Dudenbostel T, Dell'Italia LJ, Cartmill F, Zhang B, et al. Refractory hypertension: Definition, prevalence, and patient characteristics. J Clin Hypertens (Greenwich) 2012;14:7-12.  Back to cited text no. 16
Dudenbostel T, Siddiqui M, Gharpure N, Calhoun DA. Refractory versus resistant hypertension: Novel distinctive phenotypes. J Nat Sci 2017;3. pii: e430.  Back to cited text no. 17
Bhat A, Kuang YM, Gan GC, Burgess D, Denniss AR. An update on renal artery denervation and its clinical impact on hypertensive disease. Biomed Res Int 2015;2015:607079.  Back to cited text no. 18
Kandzari DE, Böhm M, Mahfoud F, Townsend RR, Weber MA, Pocock S, et al. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet 2018;391:2346-55.  Back to cited text no. 19
Solomonica A, Lavi S, Choudhury T, Bagur R. Renal denervation therapy beyond resistant hypertension. J Thorac Dis 2018;10:707-13.  Back to cited text no. 20
Bakris GL, Nadim MK, Haller H, Lovett EG, Schafer JE, Bisognano JD, et al. Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: Results of long-term follow-up in the Rheos pivotal trial. J Am Soc Hypertens 2012;6:152-8.  Back to cited text no. 21
Lobo MD, Ott C, Sobotka PA, Saxena M, Stanton A, Cockcroft JR, et al. Central iliac arteriovenous anastomosis for uncontrolled hypertension: One-year results from the ROX CONTROL HTN trial. Hypertension 2017;70:1099-105.  Back to cited text no. 22
Bharatia R, Chitale M, Saxena GN, Kumar RG, Chikkalingaiah, Trailokya A, et al. Management practices in Indian patients with uncontrolled hypertension. J Assoc Physicians India 2016;64:14-21.  Back to cited text no. 23
Singh S, Shankar R, Singh GP. Prevalence and associated risk factors of hypertension: A cross-sectional study in urban Varanasi. Int J Hypertens 2017;2017:5491838.  Back to cited text no. 24
Roy A, Praveen PA, Amarchand R, Ramakrishnan L, Gupta R, Kondal D, et al. Changes in hypertension prevalence, awareness, treatment and control rates over 20 years in national capital region of India: Results from a repeat cross-sectional study. BMJ Open 2017;7:e015639.  Back to cited text no. 25
Narang R, Srikant S. Implications of 2017 hypertension guidelines for Indian patients. J Pract Cardiovasc Sci 2018;4:3-5.  Back to cited text no. 26
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]


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