Variation in hypertension clinical practice guidelines: a global comparison

Hypertension is the largest single contributor to the global burden of disease, affecting an estimated 1.39 billion people worldwide and accounting for 10.4 million premature deaths per year [1, 2]. Despite the trajectory suggesting a continuing increase in hypertension prevalence globally, there are large numbers of undiagnosed and inadequately controlled hypertensive patients [3]. A 2017 multinational cross-sectional study found that 35% of individuals had hypertension, of whom 58% were receiving antihypertensive treatment, and of those on treatment, 46% did not achieve adequate blood pressure (BP) control [3].

Disparities in hypertension prevalence, awareness, management and control exist between country income settings. The age-standardised prevalence of hypertension fell by 2.6% from 2000 to 2010 in high-income countries (HICs), and rose by 7.7% in low- and middle-income countries (LMICs) over the same period [2]. As of 2015, the majority of hypertensive patients live in LMICs [4]. Additionally, awareness, treatment and control are increasing at slower rates in LMIC settings than in HICs [2].

Adequate management of hypertension improves outcomes from several major health conditions. A 2017 meta-analysis found that a 10-mmHg decrease in systolic blood pressure (SBP) significantly reduces the risk of major CVD events, coronary heart disease, stroke and heart failure, decreasing all-cause mortality by 13% in the study population [5]. Achieving adequate BP control is particularly important as hypertension and associated conditions are responsible for significant economic costs. In 2013, the combined direct (treating hypertension) and indirect (associated comorbidities) costs of managing hypertension were $51.2 billion in the USA alone [6]. It has been estimated that the costs of complications due to hypertension outweigh the cost of managing hypertension itself, indicating that effective hypertension management may have wide-reaching economic benefits to health systems [7, 8].

Efforts to improve the quality of care for patients with hypertension have, in part, involved the translation of available evidence on the effectiveness of current treatments into guidance documents for clinicians. Recent years have seen the widespread development and dissemination of clinical practice guidelines (CPG) by learned bodies, international societies and local care providers [9]. A CPG is defined by the Institute of Medicine as a “systematically developed statement that aids with clinician and patient decisions regarding specific clinical conditions” [10]. CPGs emerged as a means to standardise medical practice, ensure cost-effectiveness and enhance patient care [9].

Currently, there are many local, national and international guidelines produced by different organisations that give recommendations for the management of hypertension. Studies comparing these guidelines have shown variation in recommendations for the diagnosis, treatment and treatment targets for patients with hypertension [11‐13]. However, these studies compared a small number of guidelines, mainly from HICs and offered only a brief insight into their similarities and differences. Hence, scope exists to compare hypertension guidelines on a far larger scale and, importantly, across income settings.

As a condition for which the affected population predominantly live in LMICs, knowledge of variation in recommendations made to clinicians treating patients with hypertension in these settings remains poorly understood. This study aims to address this deficiency by examining the extent of variation across clinical practice guidelines for the management of hypertension internationally. The primary aim is to determine whether variation exists between CPGs for the management of hypertension through analysis of national and international guidelines from different income settings. Specifically, this study aims to compare the following:

The search strategy returned 974 records from MEDLINE; 17 of which met the inclusion criteria for selection. A further 31 guidelines were found through country-specific searches on Google. Details of search results are presented in Fig. 1, and the complete list and income classification of guidelines are found in Additional File 1. Forty-eight guidelines were included in the study, from 45 countries and territories. Eight (17%) were from LICs [15‐22], 10 (21%) from lower-MICs [23‐32], 11 (23%) from upper-MICs [33‐44], 17 (35%) were from HICs [45‐63] and 2 (4%) catered for varied income settings [64, 65]. The geographic location and income levels of included countries are shown in Fig. 2.

This study found that CPGs for the management of hypertension exist across all income settings; however, more guidelines were found from upper-MICs and HIC settings (61%). Moreover, of those found through our search strategy, 100% of CPGs from LICs provided guidance on multiple conditions, whereas all CPGs from HICs were specific to hypertension, suggesting a current gap in specific hypertension CPGs in LICs. This is supported by a 2016 systematic review which found that fewer hypertension guidelines were produced in LICs and lower-MICs [67]. Analysis from this study found consensus in the diagnostic thresholds and target BPs for uncomplicated hypertension but observed extensive variation in the treatment strategies recommended.

Consensus was observed between guidelines in the diagnostic threshold and staging of hypertension. Ninety-five per cent of guidelines defined hypertension as an SBP of ≥140 mmHg or a DBP of 90 mmHg. However, the latest 2017 ACC/AHA guidelines lowered this widely accepted threshold to ≥130/80 mmHg [55], influenced in part by the 2015 SPRINT, which found lower rates of cardiovascular events in those treated to lower BP targets [66]. Using a lower threshold for defining hypertension worldwide would greatly increase its prevalence, resulting in more patients becoming eligible for pharmacological therapy, thereby placing an increased burden on health systems to treat and monitor hypertension [68, 69]. Since the publication of SPRINT, no guideline other than the ACC/AHA 2017 guidelines [55], has lowered the diagnostic threshold for hypertension, despite the findings that 52% of guidelines published from 2016 onwards discussed the findings of SPRINT. It remains to be seen whether other guidelines will follow the ACC/AHA in lowering the diagnostic threshold.

Consensus was also found between guidelines on the inclusion of recommendations of lifestyle interventions to manage hypertension, being advised in 98% of guidelines. This guidance is in line with extensive evidence of the importance of lifestyle modifications, such as dietary changes and exercise in reducing BP [70‐72]. Guidelines also remained somewhat consistent in recommending that drug therapy should be initiated, without a trial period of non-pharmacological interventions in cases where blood pressure is 160/100 mmHg or higher.

Four broad classifications of antihypertensives, ACEi/ARBs, CCB, beta-blocker and diuretics, were most commonly used by the 48 guidelines examined but in very different sequences and combinations. The greatest level of variation was observed within second-step therapy, where 17 different combinations of pairs of drugs were recommended. In the third-step therapy, the extent of variation was reduced, with only six combinations. Evidence suggests that the effectiveness of ACEi/ARBs, CCBs and diuretics (and to a lesser extent, beta-blockers) is largely similar in lowering BP [73, 74]. This could explain the variation seen, with no strong preference amongst the different guidelines in second-step therapy. Country-specific contexts and patient-specific factors may also influence CPGs to recommend differing therapies according to their populations. For instance, the 2019 National Institute for Health and Care Excellence (NICE) guidelines [49] suggest different management strategies by ethnicity; however, there is a need for further robust studies to determine whether antihypertensive treatment outcomes vary in different ethnic populations [75].

Differences were apparent across country income settings, with an increased level of clinician choice in drug therapy options with increasing affluence. For instance, in the first-step, there was a trend towards LICs recommending diuretics, lower-MICs offering a choice between a diuretic and a CCB and upper-MICs and HICs advising any one of an ACEi, ARB, CCB and diuretic. A systematic review found that allowing clinicians’ greater autonomy in choice of management in a CPG can encourage adherence to guidelines. However, this review was primarily based on studies of physicians from HICs and so may not be generalisable to other healthcare workers and income contexts [76]. The benefits of restrictive or permissive guidelines across clinical contexts and guideline users remain an important and as yet unanswered question.

Greater flexibility in the choice of drugs may reflect the cost and accessibility of BP therapies in different contexts. There was a clear preference for diuretics and CCBs seen amongst LICs and lower-MICs for first- and second-step therapy. Diuretics are one of the least expensive antihypertensive classes [77]; based on the British National Formulary prices, thiazide diuretics (bendroflumethiazide) are the least expensive at £0.33 per pack, followed by CCBs (amlodipine) at £0.46, beta-blockers (atenolol) at £0.63 and thiazide-like diuretics (indapamide) at £0.70. In comparison, ACEi (ramipril) are priced at £2.10 and ARBs (losartan) at £5.09 [78]. At a population level, these translate to large differences in cost and could explain the preferential recommendation of diuretics and CCBs in lower-income contexts, as well as the preference of ACEi to ARBs.

CPGs from higher-income contexts were more likely to recommend initiating dual-drug therapy at a BP ≥160/100 mmHg. Recent evidence suggests that most patients will require two drug classes in order to achieve adequate BP control [79, 80]. CPGs from lower-income settings may have opted for the initiation with monotherapy again due to barriers including the low availability of affordable drugs [2]. Studies have shown that low- and middle-income countries often closely follow the release of guidelines from high-income regions [67], for instance, the 2016 Government of India Hypertension CPG [25] from this study, explicitly states that the guideline is “adopted and/or adapted from existing evidence-based guidelines”, including the European Society of Cardiology/European Society of Hypertension (ESC/ESH), Joint National Committee (JNC) and NICE guidelines [57, 81, 82]. The Indian guidelines made it clear that they chose aspects from each of these guidelines which were best suited to their particular context. Changes such as the first-line use of combination therapy as recommended by HIC guidelines may not be feasible in low-resource regions. Recognising these difficulties, the ISH 2020 [65] guidelines have produced “essential” recommendations for lower-income settings, which advocate the use of any available antihypertensives, compared to “optimum” recommendations, in order to act as a global resource; this was the only guideline assessed by this study to use this approach.

For patients that were hypertensive, most CPGs recommended a target BP of less than 140/90 mmHg whilst 9% of guidelines recommended a target of < 130/80 mmHg. The ESC/ESH 2018 guidelines recommended lower targets of SBP between 120 and 129 mmHg and a DBP between 70 and 79 mmHg in patients under 65 years [56]. The lower BP targets recommended by these guidelines are partly influenced by findings from SPRINT, where lower rates of fatal and non-fatal cardiovascular events and deaths were observed in cohorts treated to a target systolic BP of less than 120 mmHg, compared to less than 140 mmHg [66]. However, the methodology used in BP measurement may not be applicable to routine clinical practice [83], and following the publication of SPRINT, a Cochrane review updated in 2017, 2018 and 2020 based on six different randomised controlled trials (RCTs) showed no reduction in total mortality or serious adverse events when treating to a target less than 135/85 mmHg [84‐86]. The current mixed and evolving evidence regarding optimal BP targets offers a potential reason behind the variations in targets recommended by different CPGs. It is of note that most CPGs (88%) recommended a target BP for hypertensive patients that was identical to their diagnostic threshold for hypertension.

Many CPGs recommended different management strategies for elderly patients, with most opting for a higher BP target of < 150/90 mmHg. Higher targets may result from a trade-off between achieving adequate BP control and minimising adverse drug effects, which are more common in elderly patients [87]. There was a significant variation in the definition of the term “elderly”, ranging from age ≥ 55 to ≥80 years between CPGs. No clear correlation to income settings was seen between the age definitions chosen by guidelines. It may partly be attributed to variation in life expectancy across the countries from which CPGs were identified, and some CPGs explicitly mention their populations’ life expectancy when determining the cut-off age [60]. In addition to differing thresholds for the elderly, many guidelines also included specific thresholds for comorbidities, including diabetes, chronic kidney disease and cardiovascular disease. There was a general consensus towards lower target BPs in these groups (BP < 130/80 mmHg) which could reflect the need for more stringent BP control in these high-risk patients [88].

Our study highlights extensive international variation in guidelines for the management of hypertension both within and between income levels. Variation within countries was also observed, in the case of the USA with the AHA/ACC 2017 and JNC 2014 offering different diagnostic thresholds and target BP recommendations [55, 57]. As CPGs aim to be implementable digests of the best available evidence, the observed variation may represent the complex conflict between currently available evidence and what may be achieved at scale in local contexts. Additionally, what is known about the treatment of hypertension is ever-changing with the emergence of new scientific studies that may conflict with or support existing literature. A degree of dissensus between guidelines is therefore expected where the underlying evidence base for a condition is itself in flux.

The clinical guidelines featured in this study are expected to support clinicians’ decision-making across all aspects of care from the diagnosis of a condition to its treatment and monitoring. Whilst evidence from robust clinical studies may support certain crucial aspects of this process, other areas may be relatively neglected by academic scrutiny. A study analysing the evidence base of ACC/AHA 2008 guidelines found that only 11% of recommendations were made based on very strong evidence, whereas a median of 48% of recommendations was based on weaker evidence. This finding suggests that the production of a clinical guideline for the treatment of hypertension cannot be solely reliant on robust clinical evidence and that expert opinion and organisational preference may play a role in producing guidelines [89]. Similarly, the dominance of hypertension research from high-income settings results in new evidence answering questions of particular relevance to a minority of the global hypertensive population, using treatment strategies that may not be applicable to the local logistical and financial constraints of the global majority. Guidelines especially in lower-income settings may focus on what is most feasible for the particular resource setting as opposed to the optimal.

The inclusion of guidelines that are written only in English led to the exclusion of data from non-English-speaking settings. In addition, as the search strategy did not exhaustively examine all online content, eligible guidelines may have been missed by the search, particularly guidelines that encompass recommendations for multiple conditions which may not have included the terms “hypertension” or “blood pressure” in their titles or those that did not identify themselves as a guideline. Guidelines from some settings may have only been available as hard copies and would have been missed in the search strategy. As a result, the methodology may have been biassed towards including CPGs from higher-income settings. However, the aim was not to exhaustively identify all guidelines, but to provide relative comparisons between guidelines in a range of different income settings, which were all represented. In addition, this study did not seek to explore the quality and evidence base behind each CPG or to identify the extent to which these guidelines are followed in their local contexts, which were outside of the scope of the present study. Our analysis also focusses on the main thresholds and treatment presented in guidelines, which may differ for specific patient groups and in the presence of other co-morbid conditions, such as diabetes.

This study objectively characterised the variation between hypertension guidelines globally, but further research is needed to explore the underlying reasons for the divergence seen between CPGs. The evidence base used in the specific recommendations in CPGs will vary, highlighted by our findings that only half of the guidelines published in the year following the SPRINT trial included reference to its findings, and further research exploring the difference in the evidence base used in guideline creation is needed. Further qualitative research should also be conducted into the creation, utilisation and perception of hypertension CPGs by healthcare practitioners across a range of income settings, and how local context influences recommendations. In addition, whilst this study outlines variations in hypertension guidelines on a national and international level, there is further scope to assess the variation at a more local scale, within countries.

This study identified 48 national and international guidelines for the management of hypertension. BP thresholds for the diagnosis and staging of hypertension, as well as BP target recommendations, were largely consistent across guidelines and across income settings. However, recommendations on antihypertensive drug therapy at each treatment step differed greatly, with guidelines from higher-income settings offering greater clinician autonomy in choice of antihypertensive drugs and dual-combination therapies, in contrast to lower-income settings, which may reflect drug costs or availability. The variation seen may represent the lack of a robust evidence base on management, particularly for lower-income settings, given research is focused on higher-income countries. Further research is needed to explore the reasons for such divergence in guidelines to better inform those involved in their creation and the clinicians using them.