Nonpharmacological treatment of resistant hypertension: a systematic review

Abdallah M Kamal; Mohamed N. W. Hassan

doi:10.4103/mmj.mmj_298_19

ORIGINAL ARTICLE

Year : 2021 | Volume : 34 | Issue : 4 | Page : 1214-1221

Nonpharmacological treatment of resistant hypertension: a systematic review

Abdallah M Kamal¹, Mohamed N. W. Hassan²
¹ Department of Cardiology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
² Department of Cardiology, Giza General Hospital, Giza, Egypt

Date of Submission	13-Sep-2019
Date of Decision	03-Oct-2019
Date of Acceptance	12-Oct-2019
Date of Web Publication	24-Dec-2021

Correspondence Address:
Mohamed N. W. Hassan
MBBCh, Department of Cardiology, Giza General Hospital, Giza
Egypt

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/mmj.mmj_298_19

Abstract

Objective
The aim was to review the studies on nonpharmacological treatment of resistant hypertension (R-HTN).
Materials and Methods
A systematic search of MEDLINE (PubMed, Medscape, Science Direct, and EMF-Portal) and Internet was conducted on all articles published from 1986 to 2019. English-language reports of R-HTN were searched. The initial search presented 112 articles, where 31 fulfilled the inclusion criteria. Articles not reporting on the R-HTN in the title or abstract were not included. A total of 15 independent investigators extracted data on methods. Comparisons were made by structured review with the results tabulated. A total of seven studies were about R-HTN (epidemiology, prevalence, prognosis, and etiology), nine studies emphasized R-HTN and cardiovascular complications, and 15 studies emphasized nonpharmacological treatments of R-HTN.
Findings
The recommended lifestyle measures that have been shown to reduce blood pressure (BP) are salt restriction, moderation of alcohol consumption, high consumption of vegetables and fruits, weight reduction and maintaining an ideal body weight, and regular physical activity. In addition, tobacco smoking has an acute prolonged presser effect that may raise daytime ambulatory BP, but smoking cessation and other lifestyle measures are also important beyond BP.
Conclusion
This review found that nonpharmacological methods for treatment of R-HTN show great promise despite some open questions concerning their long-term effects and procedural safety. There are sufficient data to suggest that certain lifestyle modifications, such as weight loss and sodium intake reduction, are efficacious in lowering BP, reducing progression of pre-HTN to HTN, and perhaps diminishing long-term risk of CV events. However, the effectiveness of such lifestyle modifications needs to be further established in population-based studies, as implementation of healthier lifestyles is challenging.

Keywords: cardiovascular complications, epidemiology, etiology, nonpharmacological treatment, resistant hypertension

How to cite this article:
Kamal AM, Hassan MN. Nonpharmacological treatment of resistant hypertension: a systematic review. Menoufia Med J 2021;34:1214-21

How to cite this URL:
Kamal AM, Hassan MN. Nonpharmacological treatment of resistant hypertension: a systematic review. Menoufia Med J [serial online] 2021 [cited 2022 May 26];34:1214-21. Available from: http://www.mmj.eg.net/text.asp?2021/34/4/1214/333235

Introduction

Resistant hypertension (R-HTN) is defined as the failure to reach a target blood pressure (BP) despite adherence to a regimen of the maximum tolerated doses of three antihypertensive medications, one of which is a diuretic ^[1]. International guidelines include different definitions of R-HTN. According to American guidelines, R-HTN is a clinical condition characterized by the presence of BP values above the recommended limits of the reference values BP 140/90 mmHg ^[2]. A considerable number of patients fail to reach target blood pressure ranges despite lifestyle advice and standard medical therapy, one of which is represented by a diuretic, in adequate doses ^[3]. The American Heart Association considers 'resistant' those who do not achieve BP control, with office BP of 140/90 or 130/80 mmHg in patients with diabetes mellitus or chronic kidney disease, in spite of a drug regimen that includes at least three distinct classes of antihypertensive drugs, prescribed in optimal doses and that ideally include a diuretic. We also need to consider 'resistant' patients those reaching target pressure with the use of four or more drugs ^[4]. Finally, the British guidelines indicate as 'resistant' patients those whose BP values do not fall below the target BP despite the consumption of four or more antihypertensive agents. It is estimated that 20–30% of patients with HTN have R-HTN. Age and obesity are strong risk factors, and the incidence and prevalence of R-HTN may be rising as the population ages and the number of people who are overweight increases ^[5],[6].

HTN is the most common chronic disease, affecting nearly 29% of the adult population. Once considered a benign, compensatory mechanism for ageing, high BP is now recognized as an important risk factor for cardiovascular disease. It is estimated that inadequate BP control is responsible for 62% of cases of cerebrovascular disease, 49% of cases of ischemic heart disease, and 7.2 million deaths per year in the USA ^[5],[6]. Despite increasing awareness and available medical regimens, BP control is far from optimal. Only 25–30% of patients with HTN are thought to achieve the target BP of less than 140/90 mmHg. Before a patient can be labeled as having R-HTN, apparent or pseudo-R-HTN must be excluded. Most often, pseudo-R-HTN arises from poor office BP measurement technique, the 'white coat' effect, poor patient concordance with prescribed therapy, or a suboptimal antihypertensive regimen ^[1]. Medical professionals must also recognize and accept that 'clinical inertia' has an important role to play in the suboptimal management of HTN, particularly when patients require multiple drugs. The term clinical inertia can encompass a poor knowledge of clinical guidelines, a misguided acceptance of elevated BP, or an underestimation of cardiovascular disease risk, all of which can lead to suboptimal BP treatment ^[4]. The aim of this work was to review the studies on nonpharmacological treatment of R-HTN.

Materials and methods

Data sources

A systematic search on nonpharmacological treatments of R-HTN using MEDLINE (PubMed, Medscape, Science Direct, and EMF-Portal) and internet was conducted on all articles published from 1986 to 2019. During the research, the focus was on epidemiology/prevalence/prognosis/etiology/R-HTN and cardiovascular complications/nonpharmacological treatments of R-HTN. Additional records were identified by reference lists in retrieved articles. The search was established in the electronic databases from 1986 to 2019.

Study selection

Eligible articles were published in peer-reviewed journals and written in English. Articles not reporting on R-HTN in the title or abstract were excluded. Full-text articles were screened, and the final inclusion decisions were made according to the following criteria: original studies; systematic reviews or meta-analyses; primary or first-line treatment and, if necessary, secondary treatment described; and treatment success, complications, and adverse effects described.

Data extraction

Articles not reporting on R-HTN in the title or abstract were excluded. A total of 15 independent investigators extracted the articles and excluded articles based on extracted data on methods, health outcomes, report without peer-review, not within national research program, letters/comments/editorials/news, and studies not focused on R-HTN.

The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the Evidence Pyramid ^[7].

US Preventive Services Task Force ^[7] criteria are as follows:

Level I: evidence obtained from at least one properly designed randomized controlled trial
Level II-1: evidence obtained from well-designed controlled trials without randomization
Level II-2: evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
Level III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

Study quality assessment

Quality of all the studies was assessed. Important factors included study design, ethical approval, calculation of evidence power, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.

Data synthesis

A structured systematic review was done with the results tabulated. Overall, seven authors emphasized R-HTN (epidemiology, prevalence, prognosis, and etiology), nine studies emphasized R-HTN and cardiovascular complications, and 15 studies emphasized nonpharmacological treatments of R-HTN.

Results

Study selection and characteristics

In total 112 potentially relevant publications were identified; 81 articles were excluded as they did not fulfill our inclusion criteria. Overall, 31 studies were reviewed as they met the inclusion criteria. Most of the studies examined epidemiology, prevalence, prognosis, and etiology of R-HTN; R-HTN in relation cardiovascular complications; and non-pharmacological treatments of R-HTN. Regarding these studies, there were two prospective studies ^[3],[8] that come in level II-2 or (level B). We found that HTN is the most common condition managed at primary care level. It accounts for 8.6% of all visits to a primary care physician. HTN affects 32% of adults in western society, two-thirds of who are poorly controlled. In a population of 1836 patients, there was a 47% increased rate of death and cardiovascular disease. Another study examined the prognosis of R-HTN in 742 patients, excluding those with white coat R-HTN. Moreover, four randomized control studies ^{[9],[10],[11],[12]} come in level I or (level A), which reported that 10% of HTN patients in westernized countries have R-HTN. Moreover, there was a prevalence of 12.2% on clinical readings alone, but 37.5% of these patients were found to have white coat HTN after undergoing ambulatory blood pressure monitoring (ABPM), reducing the true prevalence to 7.6%. Even this estimate did not account for those who are nonadherent to therapy. There was an increased rate of cardiovascular disease events of 2.9 times, but this study was unable to account for patients who were pseudoresistant due to nonadherence. Moreover, one case analysis ^[5],[6] came in the second level regarding the pyramid of EBM and reported that in most cases the pathogenesis of R-HTN is uncertain. Only in a minority of instances is the problem owing to secondary HTN. In the absence of a secondary cause, the condition is most likely multifactorial. Proposed mechanisms include genetic factors, aberrant sympathetic nervous system activation, and altered renal sodium and water handling owing to changes in the renin-angiotensin-aldosterone system [Table 1]. Regarding R-HTN and cardiovascular complications, there were three cohort or case–control studies ^{[13],[14],[15]} that come in level II-2 or (level B) and reported that left ventricular hypertrophy (LVH) is also related to other transoesophageal doppler (TOD) and cardiovascular markers of worse prognosis. Left ventricular mass and diastolic dysfunction can be reverted, independent from BP reduction, which may reveal a new bridge between cause and effect in transoesophageal doppler (TOD) development. In a previous Refractory Hypertension (RHT) study of 556 patients evaluated after a median follow-up of 4.8 years, the crude incidence rate of total cardiovascular events was 4.32 per 100 patient-years of follow-up, with a total of 44 Coronary Artery Disease (CAD) events. Moreover, three cases or prospective studies ^{[16],[17],[18],[19]} come in level II-2 or (level B), and they found that in 705 patients with Refractory Hypertension (RHT), 534 had echocardiographic LVH; microalbuminuria and high C-reactive protein were independently associated with LVH diagnosis. Moreover, 1.1% of 10 001 individuals were considered as having apparent treatment-R-HTN. This group had a 69% increased risk of coronary heart disease mortality and a 53% higher risk of any cardiovascular event in comparison with the nonresistant subgroup. Moreover, more than 500 patients with Refractory Hypertension (RHT) showed that higher 24 h systolic blood pressure (SBP) and diastolic blood pressure (DBP) increased the risk of stroke in 42 and 62%, respectively. In addition, one randomized case–control study ^[20] came in Level I or (level A) and showed patients with Refractory Hypertension (RHT) had a 47% higher risk of cardiovascular mortality and 61% higher risk for nonfatal stroke than patients with controlled BP. Moreover, one cases analysis ^[17], which came in the second level regarding the pyramid of EBM, reported that in a large study with patients with Refractory Hypertension (RHT), using 24 h ABPM, ECG-LVH criteria were fulfilled in 18.5% of patients with true Refractory Hypertension (RHT) [Table 2]. Regarding nonpharmacological treatments of R-HTN, there was one cohort study ^[22] that come in level II-2 or (level B) which found that effective lifestyle changes may be sufficient to delay or prevent the need for drug therapy in patients with grade 1 HTN. A major drawback of lifestyle modification is the poor persistence over time. Moreover, there were eight randomize case–control studies ^{[23],[24],[25],[26],[27],[28],[29],[30],[31],[32]} that come in level I or (level A), and they estimated mean SBP and DBP reductions associated with an average weight loss of 5.1 kg were 4.4 and 3.6 mmHg, respectively. In diabetic patients, the effects of modest weight loss (24 kg over 6–36 months) by dietary intervention to reduce BP were studied. However, hard outcomes were not studied in any of the included trials. In 110 diabetic patients with uncontrolled HTN, it was revealed that home BP telemonitoring combined with automated support improved BP control over home BP monitoring alone, with 51% of intervention participants achieving BP target compared with 31% of controls. However, clinical trials showed an association between reduced calcium intake and raised BP. All these behavioral strategies were very slightly better than no therapy but were no more effective than sham controls. In addition, two cases analysis studies ^[29],[33] were in the second level regarding the pyramid of EBM, and these reported that certain lifestyle modifications, such as weight loss and sodium intake reduction, are efficacious in lowering BP, reducing progression of pre-HTN to HTN, and perhaps diminishing long-term risk of cardiovascular (CV) events. However, the effectiveness of such lifestyle modifications needs to be further established in population-based studies, as implementation of healthier lifestyles is challenging. Another three randomized controlled trials ^{[34],[35],[36]} indicated significant reduction in BP of ∼32/12 mmHg in the study group patients as opposed to an increase of 1/0 mmHg in the control group measured 6 months after the procedure. No serious adverse effects such as dissection, severe worsening of renal function, or renal artery stenosis were documented. RDN therapy was applied using the Symplicity Spyral (Medtronic 8200 Coral Sea Street NE Mounds View, MN 55112/USA) multielectrode catheter and the Symplicity G3 generator (Medtronic 8200 Coral Sea Street NE) Mounds View, MN 55112). At 3 months of follow-up, the RDN group had shown statistically significant decrease in BP measurements in comparison with the sham (controlled) group [Table 3].

Table 1: Resistant hypertension (epidemiology, prevalence, prognosis, and etiology)

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Table 2: Resistant hypertension and cardiovascular complications

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Table 3: Nonpharmacological treatments of resistant hypertension

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Discussion

Resistant hypertension (epidemiology, prevalence, prognosis, and etiology)

HTN is widely encountered in primary care and is the most common condition managed at primary care level. It accounts for 8.6% of all visits to a primary care physician. HTN affects 32% of adults in western society, two-thirds of who are poorly controlled ^[9]. Its prevalence is likely to continue rising. It is estimated that ∼10% of HTN patients in westernized countries have resistant HTN. Doctors in primary care can expect to encounter R-HTN one in every 20 HTN patients, compared with higher rates in specialist clinics ^[9]. Indeed, one study by Krause et al. ^[12] identified a prevalence of 12.2% on clinical readings alone, but 37.5% of these patients were found to have white coat HTN after undergoing ABPM, reducing the true prevalence to 7.6%. Even this estimate did not account for those who are nonadherent to therapy ^[10]. Few studies have examined its true prognosis and examined the prognosis of R-HTN while excluding patients deemed nonadherent to medication owing to failure to collect medication prescription refills. In a population of 18 036 patients, those with R-HTN were found to have a 47% increased rate of death and cardiovascular disease (defined as all-cause mortality and incident cardiovascular events [non-fatal MI, congestive heart failure, stroke, or disease (CK)] compared with those with non-R-HTN ^[8]. Another study by Romano et al. ^[3] examined the prognosis of R-HTN in 742 patients, excluding those with white coat R-HTN ^[3]. They demonstrated an increased rate of cardiovascular disease events of 2.9 times (compared with controlled HTN individuals), but this study was unable to account for patients who were pseudoresistant owing to nonadherence ^[11]. In most cases, the pathogenesis of R-HTN is uncertain. Only in a minority of instances is the problem owing to secondary HTN. In the absence of a secondary cause. the condition is most likely multifactorial. Proposed mechanisms include genetic factors, aberrant sympathetic nervous system activation, and altered renal sodium and water handling owing to changes in the renin–angiotensin–aldosterone system ^[5],[6].

Resistant hypertension and cardiovascular complications

In previous studies with general HTN, concentric hypertrophy was more consistently associated with increased cardiovascular risk and with the degree of BP load. LVH is also related to other transoesophageal doppler (TOD) and cardiovascular markers of worse prognosis ^[13]. In a cross-sectional study with 705 patients with RHT, 534 had echocardiographic LVH; microalbuminuria and high C-reactive protein were independently associated with LVH diagnosis. When LVH is assessed by ECG (ECGLVH), although it has less sensitivity, it keeps its prognostic importance ^[16]. In a large study with patients with RHT, using 24-h ABPM, ECG-LVH criteria were fulfilled in 18.5% of patients with true RHT ^[17]. Studies recently conducted in patients after renal sympathetic denervation have demonstrated that left ventricular mass and diastolic dysfunction can be reverted, independent from BP reduction, which may reveal a new bridge between cause-and-effect in TOD development ^[14]. Similarly, in a case–control study, patients with primary aldosteronism had significantly greater left ventricular measurements including Left ventricular mass index (LVMI) compared with control group ^[15]. In a previous RHT cohort study in which 556 patients were evaluated after a median follow-up of 4.8 years, the crude incidence rate of total cardiovascular events was 4.32 per 100 patient-years of follow-up, with a total of 44 Coronary Artery Disease (CAD) events (23 acute myocardial infarctions, 16 myocardial revascularizations, and five sudden deaths) ^[21]. Moreover, a randomized, open-label, blinded endpoint study that enrolled 22 576 patients (>50 years) with HTN and coronary artery diseases at 862 centers in 14 countries demonstrated that patients with RHT had a 47% higher risk of cardiovascular mortality and 61% higher risk for nonfatal stroke than patients with controlled BP ^[20]. In another study performed specifically in patients with coronary heart disease, 11.1% of 10 001 individuals were considered as having apparent treatment R-HTN. This group had a 69% increased risk of coronary heart disease mortality and a 53% higher risk of any cardiovascular event in comparison with the nonresistant subgroup ^[18]. Another prospective study with more than 500 patients with RHT showed that higher 24 h SBP and DBP increased the risk of stroke in 42 and 62%, respectively ^[19].

Nonpharmacological treatments of resistant hypertension

Healthy lifestyle choices can prevent or delay the onset of HTN and can reduce cardiovascular (CV) risk. Effective lifestyle changes may be sufficient to delay or prevent the need for drug therapy in patients with grade 1 HTN. A major drawback of lifestyle modification is the poor persistence over time ^[22]. The recommended lifestyle measures that have been shown to reduce BP are salt restriction, moderation of alcohol consumption, high consumption of vegetables and fruits, weight reduction and maintaining an ideal body weight, and regular physical activity. In addition, tobacco smoking has an acute prolonged presser effect that may raise daytime ambulatory BP, but smoking cessation and other lifestyle measures are also important beyond BP ^[20]. In a meta-analysis of randomized controlled trials, the mean SBP and DBP reductions associated with an average weight loss of 5.1 kg were 4.4 and 3.6 mmHg, respectively ^[23]. In a systematic review of diabetic patients, the mean weight loss after 1–5 years was 1.7 kg. A cochrane review summarized the effects of modest weight loss (24 kg over 6–36 months) by dietary intervention to reduce BP. However, hard outcomes were not studied in any of the included trials ^[24]. Long-term outcome studies of weight loss by bariatric surgery using gastric banding revealed mixed results ^[25]. In the Swedish obese patients study, after a transient lowering of BP in the first postoperative years, BP was similar in participants who underwent surgery compared with controls ^[26]. A recent randomized, controlled trial of 110 diabetic patients with uncontrolled HTN revealed that home BP telemonitoring combined with automated support improved BP control over home BP monitoring alone, with 51% of intervention participants achieving BP target compared with 31% of controls ^[27]. A randomized trial of 401 participants with uncontrolled HTN showed that an intervention using telemonitoring under primary care clinician supervision and optional patient decision support improved daytime ambulatory BP by 4.3/2 mmHg compared with usual care ^[28]. Finally, there were sufficient data to suggest that certain lifestyle modifications, such as weight loss and sodium intake reduction, are efficacious in lowering BP, reducing progression of pre-HTN to HTN, and perhaps diminishing long-term risk of cardiovascular (CV) events ^[29]. However, the effectiveness of such lifestyle modifications needs to be further established in population-based studies, as implementation of healthier lifestyles is challenging ^[33]. Moreover, clinical trials showed an association between reduced calcium intake and raised BP ^[30]. A recent review of 26 reports that met reasonable standards for scientific accuracy found that all these behavioral strategies were very slightly better than no therapy but were no more effective than sham controls ^[31]. A more recent prospective randomized controlled trial of adequate power in 99 mildly HTN men and women failed to show any reduction in BP after 4 months of such training ^[32].

The Symplicity HTN-1 was the first-in-man trial published in 2009. In this proof-of-concept trial, RDN therapy had been used among patients with resistant HTN who were selected owing to the potential clinical benefit ^[34]. Later on, the symplicity HTN-2 was a randomized-controlled, multicenter trial that has shown a significant reduction in BP of ∼32/12 mmHg in the study group patients as opposed to an increase of 1/0 mmHg in the control group measured 6 months after the procedure. No serious adverse effects such as dissection, severe worsening of renal function, or renal artery stenosis were documented ^[35]. The 3-year follow-up results of these two trials had shown long-term efficacy achieving a reduction in SBP of over 30 mmHg and in DBP of 13 mmHg as compared with baseline, with an overall good safety profile, with only one recorded dissection and two cases of kidney injury which had resolved ^[34],[35]. Another trial was to evaluate RDN therapy in the absence of any antihypertensive medication compared with a sham-controlled population. Patients in both arms had similar baseline characteristics including baseline BP. RDN therapy was applied using the Symplicity Spyral multielectrode catheter and the Symplicity G3 generator. This catheter consists of a four-electrode catheter that is positioned to deliver circumferential radiofrequency energy, and thus, it covers the four quadrants of the renal artery and branch vessels ^[36]. At 3 months of follow-up, the RDN group had shown statistically significant decrease in BP measurements in comparison with the sham-controlled group. Of note, these changes were quite modest with only 5 and 4.4 mmHg difference in SBP and DBP ambulatory measurements, respectively, between the RDN group and the sham one. Office measurements had shown a larger difference between the groups with a drop in SBP of 7.7 mmHg and DBP of 4.9 mmHg favoring the RDN group. No adverse events were recorded ^[36].

Conclusion

This review found that nonpharmacological methods for treatment of R-HTN show great promise despite some open questions concerning their long-term effects and procedural safety. There are sufficient data to suggest that certain lifestyle modifications, such as weight loss and sodium intake reduction, are efficacious in lowering BP, reducing progression of pre-HTN to HTN, and perhaps diminishing long-term risk of cardiovascular (CV) events. However, the effectiveness of such lifestyle modifications needs to be further established in population-based studies, as implementation of healthier lifestyles is challenging.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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