December 2019 • VOL. 67                                                                           Supplement to JAPI • December 2019

Editorial

Resistant Hypertension - A Quandary of its Own

R Chandni

Professor of Medicine, Government Medical College, Kozhikode, Kerala

Introduction

Systemic Hypertension is recognized as a silent killer and a major cause for premature death. An estimated 1.13 billion people worldwide have hypertension, most (two-thirds) living in low- and middle-income countries as per the WHO fact sheet of 13 September 2019.1 Though the leading cause for cardiovascular morbidity and mortality, there are many established interventions to prevent and to treat hypertension. But systemic hypertension still continues to be under diagnosed, under treated and inadequately controlled though it is easy to measure, amenable to treatment and proven to reduce the complications with treatment.

The diagnosis of systemic hypertension is based on office blood pressure in most of the situations and accurate measurement of blood pressure (BP) with the correct technique needs to be emphasised before making the diagnosis. American College of Cardiology (ACC)/American Heart Association (AHA) in 2017 defined hypertension by an average systolic BP (SBP) ≥130 mm Hg or diastolic BP (DBP) ≥80 mm Hg.2 But The European Society of Cardiology and European Society of Hypertension (ESC/ESH), as well as the National Institute for Health and Care Excellence (NICE) guidelines,3 and The Indian Guidelines on hypertension (IGH - IV)4 define hypertension using office-based blood pressure, as a systolic pressure ≥140 mmHg or diastolic pressure ≥90 mmHg in adults aged 18 years and more. In clinical practice, regardless of their observed blood pressure, patients on treatment for hypertension are usually defined as having hypertension.
In “Mumbai cohort study”, less than 20% men and women had normal BP level , with prehypertension among 40.8% men and 35.9% women and in that study group men with prehypertension had increased risk of cerebrovascular disease deaths. BP levels between 130 to 139/80 to 89 mm Hg in the Indian population caused substantial CVD, stroke, and premature mortality. Compared to normal BP, stage-II hypertension is associated with increased risk of all-cause mortality.5 Untreated hypertension is recognized as an important risk factor for hemorrhagic stroke and approximately one fourth of hemorrhagic strokes would be prevented if all hypertensive subjects received treatment.6 Females developed intracerebral bleed at a lower blood pressure measurement compared to males.7 Though the prevalence of systemic hypertension is increasing with convergence in urban-rural prevalence,8 awareness and control rates are still suboptimal and with no improvement over the years.9-11

Resistant hypertension

Resistant hypertension (RH), defined as blood pressure (BP) remaining above goal despite the use of ≥ 3 antihypertensive medications at maximally tolerated doses (one being a diuretic) or BP that requires ≥ 4 agents to achieve control. In situations where BP achieves the target values on ≥4 antihypertensive medications, those patients are grouped as controlled RH.12 The identification and treatment of RH is urgently needed because they are more prone for target-organ damage and for complications like stroke, myocardial infarction, heart failure, and/or chronic kidney disease compared with patients whose blood pressure can be easily controlled.
In clinical practice, this could be true or pseudo resistant hypertension. All the recognized reasons for pseudo resistance are to be addressed before labelling it as true resistance. Because many of the times this could be due to inadequate adherence to life style and or medications, less optimum titration of dose, failure to recognize and treat important secondary causes and/or concomitant use of medications that raise the blood pressure like NSAIDs.13 Out-of-office blood pressure monitoring (both home and ambulatory blood pressure monitoring) helps to recognize the white coat effect. Ambulatory blood pressure monitoring (ABPM) should be done in these patients in order to identify the true from pseudo resistant hypertension.

Refractory hypertension

The current definition of refractory hypertension (RfHTN) is based on failure to control BP with use of ≥5 antihypertensive agents of different classes, including a longacting thiazide-like diuretic, such as chlorthalidone and spironolactone. Patients with RfHTN, identified after routine clinical follow-up of ≥3 visits for ≥6 months, had uncontrolled BP in spite of being adherent to a regimen of ≥5 classes of antihypertensive agents, including chlorthalidone 25 mg daily and Mineralocorticoid receptor antagonists (MRA) (spironolactone, 25 mg daily, or eplerenone, 50 mg BID) without evidence of underlying secondary causes of hypertension.12,14 Obstructive Sleep Apnoea is strongly associated with hypertension and more so in patients having non dipping nocturnal blood pressure with ABPM. Continuous positive airway pressure (CPAP) treatment achieves a clinically significant reduction in blood pressure levels in those patients with RfHTN. 15

Indian data on Resistant Hypertension

There is a need for more Indian data on RH. The original article by Rajeev Gupta et al in this issue of JAPI is providing Indian data on the prevalence of resistant hypertension, from a secondary care centre. In this hospital registry based study, they have looked at the prevalence of RH by both the definitions. Patients from January 2013 to June 2017 presenting with hypertension as primary diagnosis are included and those with cardiovascular complications, chronic kidney disease, patients with known cause (secondary hypertension) and pregnancy induced hypertension are excluded in this study. By analyzing the prescription pattern, they have provided a very alarming number of one in five patients with hypertension in India are having resistant hyper t ension, needing multiple drugs to control BP and this is significantly greater among patients older than 60 y ears and in women.
This study by Rajeev Gupta et al has added an insight to this problem of RH in Indian context. We need to see this quandary more closely in future studies by identifying the true from pseudo resistant hypertension by monitoring ABPM, ensuring optimum tolerated dose of anti hypertensives, reinforcing life style modifications and ruling out all treatable causes of secondary hypertension. The group of true resistant hypertension after optimising modifiable and treatable causes will require additional drugs and if not getting controlled, that group must be considered for specific interventional studies.
With the recognition of patients with true resistant hypertension, we need to optimise the treatment as they are prone for higher target organ damage. They need more focussed life style measures, optimising weight and control of obesity, individualizing the treatment and the dose of drugs, ensuring medication adherence, excluding treatable causes of hypertension and correct BP recording, before labelling as true RH.4

Treatment of Resistant hypertension

The three classes of drugs preferred as initial option in hypertension management are a thiazide diuretic, an ACE inhibitor or angiotensin receptor blocker, and a calcium channel blocker. This preferred triple drug regimen may be changed depending on the presence of co-morbidities. β-blockers may be the preferred option if there is previous coronary heart disease or heart failure. Though Atenolol is no longer recommended in pregnancy, Labetalol an α and β blocker is the drug of choice for hypertension in pregnancy especially for the management of acuteonset, severe hypertension in pregnant women. Currently there are some evidences to suggest Spironolactone as the preferred fourth or fifth option in resistant hypertension.4,16,17 In a very small randomized controlled trial in patients with true resistant hypertension, spironolactone in dose of 50 mg is shown to be more effective than sympathetic renal denervation to reduce 24-h SBP and 24-h DBP.18 In the article by Rajeev Gupta et al in this issue of JAPI though they have not looked into the optimisation of treatment of RH, they have mentioned about the pattern of drug use in their study. Only 1.9% has received MRA namely Epleronone or Spironolactone with 66.2% Epleronone users and 33.8% Spironolactone users. Patients on MRA must be closely monitored for side effects especially hyperkalemia and it is more frequently reported in patients having chronic kidney disease, and when used along with drugs causing hyperkalemia like ACEI, ARBs or NSAIDS.
We need to get more data from clinical trials to support the clinical use of device-based approaches such as renal sympathetic denervation therapy, baroreflex activation therapy and procedures like central arteriovenous anastomosis for the treatment of RH especially in those subsets where blood pressure control is a very difficult challenge with optimum medical therapy.4
Resistant hypertension as a sub group needs to be recognized and further studied. “Resistant Hypertension in Clinical Practice in India: Jaipur Heart Watch” will definitely lead us into more research areas as there is an increase in RH among older patients and women as per this study. The prevalence of RH is different when two different definitions are used and we need to find out which is going to identify the right group of RH by planning properly conducted future research especially in Indian context. The prevalence, the predisposing factors responsible including genetic factors, prognosis and treatment modalities including interventions also need to be elucidated in future research plans.

References

1. https://www.who.int/news-room/fact-sheets/detail/ hypertension accessed on 31-10-2019.

2. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/ AAPA /ABS/ACPM/AGS/APhA/ASH/ASPC/NMA/ PCNA guideline for the prevention, detection, evaluation and management of high blood pressure in adults: executive summary. J Am Coll Cardiol 2018; 71:2199-269.

3. Williams B, Mancia G, Spiering W, Rosei EA, Azizi M, Burnier M, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 2018; 39:3021–104.

4. Indian Guidelines on Hypertension - IV 2019. http://www. japi.org/october_2019_spl/contents.html#

5. Mangesh S. Pednekar, Rajeev Gupta, Prakash C. Gupta, Association of Blood Pressure and Cardiovascular Mortality in India: “Mumbai cohort study”. American Journal of Hypertension 2009; 22:1076–1084, https://doi.org/10.1038/ ajh.2009.131.

6. Woo D, Haverbusch M, Sekar P, Kissela B, Khoury J, et al. Effect of untreated hypertension on hemorrhagic stroke. Stroke 2004; 35:1703-8 (ISSN: 1524-4628).

7. Nechikkat S, Chandni R, Sasidharan PK. Hypertension as a Risk Factor for Haemorrhagic Stroke in Females. J Assoc Physicians India 2014; 62:24-8.

8. Gupta R. Convergence in urban-rural prevalence of hypertension in India. J Hum Hypertens 2016; 30:79-82. doi: 10.1038/jhh.2015.48.

9. Gupta R. Rethinking diseases of affluence; coronary heart disease in developing countries. South Asian Journal of Preventive Cardiology 2006; 10:65-78.

10. Roy A, Praveen PA, Amarchand R, 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. Published 2017 Jul 12. doi:10.1136/bmjopen-2016-015639.

11. Anchala R, Kannuri NK, Pant H, et al. Hypertension in India: a systematic review and meta-analysis of prevalence, awareness, and control of hypertension. J Hypertens 2014; 32:1170–1177. doi:10.1097/HJH.0000000000000146.

12. Acelajado MC, Hughes ZH, Oparil S, Calhoun DA. Treatment of Resistant and Refractory Hypertension. Circ Res 2019; 124:1061-1070. DOI: 10.1161/CIRCRESAHA.118.312156.

13. Grigoryan L, Pavlik VN, Hyman DJ. Characteristics, drug combinations and dosages of primary care patients with uncontrolled ambulatory blood pressure and high medication adherence. J Am Soc Hypertens 2013; 7:471.

14. Acelajado MC, Pisoni R, Dudenbostel T, Dell’Italia LJ, Cartmill F, Zhang B, Cofield SS, Oparil S, Calhoun DA. Refractory hypertension: definition, prevalence, and patient characteristics. J Clin Hypertens (Greenwich) 2012; 14:7–12. doi: 10.1111/j.1751-7176.2011.00556.x

15. Oscullo G, Sapiña-Beltrán E, Torres G, Zaldivar E. The Potential Role of Obstructive Sleep Apnoea in Refractory Hypertension. Curr Hypertens Rep 2019; 21:57. doi: 10.1007/ s11906-019-0963-6.

16. Pio-Abreu, A & Drager LF. Resistant Hypertension: Time to Consider the Best Fifth Anti-Hypertensive Treatment. Curr Hypertens Rep 2018; 20:67. https://doi.org/10.1007/s11906- 018-0866-y.

17. Zhao D, Liu H, Dong P, Zhao J. A meta-analysis of add-on use of spironolactone in patients with resistant hypertension. Int J Cardiol 2017; 233:113-117. Epub 2016 Dec 29.

18. Oliveras A, Armario P, Clarà A, Sans-Atxer L, et al. Spironolactone versus sympathetic renal denervation to treat true resistant hypertension: results from the DENERVHTA study - a randomized controlled trial. J Hypertens 2016; 34:1863-71.