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.
2. Khanra and Duggal: Resistant hypertension
Journal of the Practice of Cardiovascular Sciences ¦ Volume 5 ¦ Issue 2 ¦ May-August 2019 77
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
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.
Yamashita et al.[10]
have developed PFK score which consists of
U pH >7, female sex, K <3.5, primary hyperaldosteronism can be
suspectedifPFKscoresarepositive.Prescribingspironolactoneahs
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?
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 BPis >140/90 withA + C + D regimen,
ABPM should be advised to rule out WCH and diuretics
should be changed to long‑acting chlorthalidone. Accuracy
of BPmeasurement, 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?
In a large community‑based study of 8295 patients with RH
classified on the basis ofABPM, de la Sierra et al.[14]
found that
Figure 2: Normal and abnormal pattern of ambulatory blood pressure
monitoring.Figure 1: Spectrum of resistant hypertension as per ambulatory blood
pressure monitoring. RH: Resistant hypertension.
[Downloaded free from http://www.j-pcs.org on Tuesday, October 1, 2019, IP: 117.237.240.146]
3. Khanra and Duggal: Resistant hypertension
Journal of the Practice of Cardiovascular Sciences ¦ Volume 5 ¦ Issue 2 ¦ May-August 201978
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?
One subset ofTRH patients are not amenable to achievement of
target BPdespite 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 BPcontrol
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 ofAlabama
at has proposed a classification of HTN according to number
of drugs [Figure 4].[17]
Dudenbostel et al. compared the profile
of RfH toTRH patients and found that RfH patients are younger
with low renin and high sympathetic activity [Figure 5].[17]
Figure 6 summarizes the approach to RH.
What Can be the Last Resort for Refractory
Hypertension Patients?
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
Figure 4: Classification of hypertension according to number of drugs.
Figure 3: Causes of secondary hypertension.
Figure 5: Comparison of true resistant hypertension and refractory
hypertension.
[Downloaded free from http://www.j-pcs.org on Tuesday, October 1, 2019, IP: 117.237.240.146]
4. Khanra and Duggal: Resistant hypertension
Journal of the Practice of Cardiovascular Sciences ¦ Volume 5 ¦ Issue 2 ¦ May-August 2019 79
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
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
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.
Ethics clearance
Ethical clearance taken.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
1. Anchala R,Kannuri NK,Pant H,Khan H,Franco OH,DiAngelantonio 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.
2. Guideline for the Prevention, Detection, Evaluation, and Management
of High Blood Pressure in Adults; 2017.
3. 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.
4. 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.
5. 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.
6. 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.
7. George J, MacDonald T. Home blood pressure monitoring. Eur Cardiol
2015;10:95‑101.
Figure 6: Approach to resistant hypertension.
[Downloaded free from http://www.j-pcs.org on Tuesday, October 1, 2019, IP: 117.237.240.146]
5. Khanra and Duggal: Resistant hypertension
Journal of the Practice of Cardiovascular Sciences ¦ Volume 5 ¦ Issue 2 ¦ May-August 201980
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. National Institute of Health and Care Excellence: Hypertension in
adults: diagnosis and management (CG127). 2016.
14. 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.
15. Obara T, Ohkubo T, Asayama K, Metoki H, Inoue R, Kikuya M, et al.
Homebloodpressuremeasurementsassociatedwithbetterbloodpressure
control: The J‑HOME study. J Hum Hypertens 2008;22:197‑204.
16. 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.
17. Dudenbostel T, Siddiqui M, Gharpure N, Calhoun DA. Refractory
versus resistant hypertension: Novel distinctive phenotypes. J Nat Sci
2017;3. pii: e430.
18. 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.
19. 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.
20. Solomonica A, Lavi S, Choudhury T, Bagur R. Renal denervation
therapy beyond resistant hypertension. J Thorac Dis 2018;10:707‑13.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. Narang R, Srikant S. Implications of 2017 hypertension guidelines for
Indian patients. J Pract Cardiovasc Sci 2018;4:3‑5.
[Downloaded free from http://www.j-pcs.org on Tuesday, October 1, 2019, IP: 117.237.240.146]