Concordance of recommendations across clinical practice guidelines for the management of hypertension in Southeast Asia with internationally reputable sources

Objectives This study aimed to assess the rate of concordance, and to investigate sources of non-concordance of recommendations in the management of hypertension across CPGs in Southeast Asia, with internationally reputable clinical practice guidelines (CPGs). Methods CPGs for the management of hypertension in Southeast Asia were retrieved from the websites of the Ministry of Health or cardiovascular specialty societies of the individual countries of Southeast Asia during November to December 2020. The recommendations for the management of hypertension specified in the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guideline and the 2018 European Society of Cardiology (ESC)/European Society of Hypertension (ESH) guideline were selected to be the reference standards; the recommendations concerning the management of hypertension in the included CPGs in Southeast Asia were assessed if they were concordant with the reference recommendations generated from both the 2017 ACC/AHA guideline and the 2018 ESC/ESH guideline, using the population (P)-intervention (I)-comparison (C) combinations approach. Results A total of 59 reference recommendations with unique and unambiguous P-I-C specifications was generated from the 2017 ACC/AHA guideline. In addition, a total of 51 reference recommendations with unique and unambiguous P-I-C specifications was generated from the 2018 ESC/ESH guideline. Considering the six included CPGs from Southeast Asia, concordance was observed for 30 reference recommendations (50.8%) out of 59 reference recommendations generated from the 2017 ACC/AHA guideline and for 31 reference recommendations (69.8%) out of 51 reference recommendations derived from the 2018 ESC/ESH guideline. Conclusions Hypertension represents a significant issue that places health and economic strains in Southeast Asia and demands guideline-based care, yet CPGs in Southeast Asia have a high rate of non-concordance with internationally reputable CPGs. Concordant recommendations could perhaps be considered a standard of care for hypertension management in the Southeast Asia region. Supplementary Information The online version contains supplementary material available at 10.1186/s12872-021-02054-x.


Introduction
Over the past decade, Southeast Asia has undergone significant socioeconomic development, which led to changes in lifestyle that translated into a growing prevalence of chronic non-communicable diseases. Approximately one-third of adults in the region have hypertension and close to 1.5 million deaths are attributed to hypertension annually [1]. Hypertension represents a significant issue that places health and economic strains in Southeast Asia, as this is partly due in part to absent or poor disease management, with rates of uncontrolled hypertension reported in some Southeast Asian countries were as high as 80% [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].
Proper management of hypertension which could reduce the risk of cardiovascular morbidity and mortality, signifies the importance of clinical practice guidelines (CPGs) to guide clinicians in the accurate diagnosis and appropriate treatment of patients with hypertension [21]. By far the two most well-established CPGs for the management of hypertension are the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guideline [22] and the 2018 European Society of Cardiology (ESC)/European Society of Hypertension (ESH) guideline [23]. The 2017 ACC/AHA guideline [22] recommended tighter blood pressure control (systolic blood pressure of < 130 mmHg and diastolic blood pressure of < 80 mmHg), which is backed by several meta-analyses of observational studies which reported significantly higher hazards for the development of cardiovascular disease and stroke with blood pressure of ≥ 120-129/80-84 mm Hg relative to blood pressure of < 120/80 mm Hg (hazard ratios ranged from 1.1 to 1.5) [24]. In addition, evidence for the positive outcomes from tighter blood pressure control was also reported in the Systolic Blood Pressure Intervention (SPRINT) trial [25].
Rather than focusing on tighter blood pressure control, the 2018 ESC/ESH guideline [23] defines hypertension based on the level of blood pressure at which the benefits either with lifestyle interventions or treatment with antihypertensive agents, outweighed their risks. Indeed, such recommendation is supported by the meta-analyses of randomized controlled trials (instead of the meta-analyses of observational studies cited in the 2017 ACC/ AHA guideline [22]), which demonstrated that treatment of patients with blood pressure of ≥ 140/90 mm Hg was considered beneficial [23]. Moreover, observational cohort studies with high-risk and older population, as referenced in the 2017 ACC/AHA guideline [22], could increase the detection of statistical significance over a shorter follow-up period. The discrepancies in the type of evidence used between the 2017 ACC/AHA guideline [22] and the 2018 ESC/ESH guideline [23] may provide insight as to why the recommended blood pressure thresholds for the treatment and diagnosis hypertension differ between the two well-established CPGs.
Although low-and middle-income regions including countries in the Southeast Asia have developed CPGs for the management of hypertension, they often follow closely the release of CPGs from the high-income regions, and these CPGs are adopted/adapted from those of the high-income regions in many instances [26]. Nevertheless, common in both low and high-income regions, the non-concordance in recommendations in the CPGs for the management of hypertension frequently cause confusion among health care providers [27]. Only a few studies had addressed if the recommendations in the CPGs for management of hypertension originated from the Southeast Asia are concordant with internationally reputable sources.
Al-Ansary et al. [28] compared the recommendations in 11 CPGs for the management of hypertension, one of which was the CPG originated from Southeast Asia (Malaysia). There were disagreements in terms of the recommendations for pharmacotherapy of hypertension. For instance, it was reported that the included CPGs were discrepant in the strategies for adjustment of antihypertensive agents. Most CPGs recommended adding an antihypertensive agent from another class if the blood pressure has not been well-controlled; but few CPGs recommended substituting with another antihypertensive agent, with or without increasing the dose of the initial antihypertensive agent. Moreover, recommendations related to the combination of antihypertensive agents also differed across CPGs.
It is noteworthy that concordance of recommendations across CPGs is one of the factors that could affect the implementation of the recommendations specified in CPGs in the clinical practice. Therefore, this study aimed to assess the rate of concordance of recommendations in the management of hypertension across CPGs in Southeast Asia with internationally reputable CPGs and to investigate the sources of non-concordance in recommendations in the management of hypertension across CPGs in Southeast Asia with internationally reputable CPGs.

Identification and selection of clinical practice guidelines
Two investigators (CSK and SSH) independently searched and identified the CPGs for the management of hypertension in Southeast Asia during November 2020 to December 2020 from the websites of the Ministry of Health or cardiovascular specialty societies of the individual countries of Southeast Asia. If the CPGs cannot be identified from the websites, the Ministry of Health or cardiovascular specialty societies of the respective country was approached formally by email to request a softcopy of the CPG. Only the latest version of CPGs was selected for inclusion if the CPGs had several versions.
In order to ensure all potentially relevant CPGs had been identified, the two investigators (CSK and SSH) also independently conducted targeted searching of CPGs by country in Turning Research into Practice database, Google Scholar database, and Google search engine using the keywords "hypertension", "high blood pressure", "clinical practice guideline", "guideline", "recommendation", and "consensus". The reference lists of included CPGs were also manually examined for potentially relevant CPGs. Any discrepancies in the selection of CPGs for inclusion were resolved through consensus discussion with a third investigator.
The eligibility criteria for the selection of CPGs from each respective country in Southeast Asia included: (1) CPGs that were currently active for use by health care providers in the respective country at the time of selection; (2) CPGs that were published/endorsed by the Ministry of Health or cardiovascular specialty societies of the respective country; (3) CPGs that were developed or updated in or after 2010; (4) CPGs that were published in official (translated) language of English or Malay; (5) CPGs that were regarded as the principal source of guidance for clinical care of hypertension by health care practitioners in the respective country at the time of selection; and (6) CPGs that addressed the general management of hypertension (e.g., goals blood pressure or pharmacotherapy in patients with hypertension with or without comorbidities).
Exclusion criteria included: (1) CPGs that were published in official (translated) languages other than English or Malay; (2) CPGs that addressed the management of hypertension in patients with specific comorbidities (e.g., diabetes, stroke, or cardiovascular disease); and (3) documents with single author or publications such as summaries of CPGs and non-official translated versions of CPGs.

Data extraction from the included clinical practice guidelines
Two investigators (CSK and SSH) independently performed data extraction from the included CPGs with a pre-designed data extraction form. Discrepancies in the extracted data were resolved by consensus, involving other investigators if necessary. The following information was extracted: the publication year, status of the CPG (newly developed or updated from the previous version), the type of elaboration organization (governmental institution or specialty society), availability of funding/ sponsorship, size of CPG development group, total number of cited references, total number of cited systematic reviews, total number of cited Cochrane reviews, and evidence classification method.

Reference recommendation specification
The 2017 ACC/AHA guideline [22] and the 2018 ESC/ ESH guideline [23] for the management of hypertension represented two of the most influential CPGs in the domain of hypertension which could inform the treatment practice of hypertension globally at the time of conducting this study. In fact, both the 2017 ACC/AHA guideline [22] and the 2018 ESC/ESH guideline [23] for the management of hypertension were in the top 5% of all research outputs ever tracked by Altmetric and has been cited in more than 2,400 publications and 1,800 publications respectively, as tracked by Web of Science, as of November 2020. Therefore, the recommendations for the management of hypertension specified in the 2017 ACC/ AHA guideline [22] and the 2018 ESC/ESH guideline [23] were selected to be the reference standards (aka reference recommendations); the recommendations concerning the management of hypertension in the included CPGs in Southeast Asia were assessed if they were concordant with the reference recommendations generated respectively from the 2017 ACC/AHA guideline [22] and the 2018 ESC/ESH guideline [23].
However, differences in the interpretations of population, intervention, and comparator concepts for a given reference recommendation precluded direct analysis of concordance of recommendations. In order to avoid ambiguity that might arise, generation of the reference recommendations was adapted from a previously validated population (P)-intervention (I)-comparison (C) combinations approach [29] in order to provide a coherent framework to define the frames of reference for the interpretation of reference recommendations [29]. The population (P) was (adapted from a previous similar study [29]) for whom the recommendations from either the 2017 ACC/AHA guideline [22] or the 2018 ESC/ ESH guideline [23] were intended; the intervention (I) was defined as the standard approach adopted in either the 2017 ACC/AHA guideline [22] or the 2018 ESC/ESH guideline [23]; whereas the comparator (C) was defined as the approach in contrast to the standard approach specified in either the 2017 ACC/AHA guideline [22] or the 2018 ESC/ESH guideline [23].

Coding of reference recommendations
For each reference recommendation, a coder, who was a registered primary care pharmacist actively practicing in the management of hypertension, compared and coded the recommendation from each of the included CPGs from Southeast Asia in two steps. First, the coder determined whether a given reference recommendation was adequately addressed in the included CPGs from Southeast Asia to allow for concordance mapping; if it was not adequately addressed, the recommendation was marked 'out of scope' for that CPG and ruled out from further analysis. Second, each in-scope reference recommendation was coded as: 'for' if the CPG from Southeast Asia recommended the intervention (I) over the comparator (C), 'against' if the CPG from Southeast Asia recommended the comparator (C) over the intervention (I), 'insufficient' if the CPG from Southeast Asia did not recommend 'for' or 'against' the intervention (I) due to insufficient evidence, but the P-I-C specification was in-scope, or 'different' if the assertion from the CPG from Southeast Asia could not be classified as 'for' , 'against' , or 'insufficient' .
A code reviewer, who was a registered clinical pharmacist with clinical experience in the management of hypertension, checked the codings of the coder for accuracy. Subsequently, an investigator with academic background reviewed the codings, and any discrepancy identified was resolved by consensus. Final codings were confirmed when a full consensus was achieved.
After confirmation of the codings for every reference recommendation, rate of concordance was calculated. CPG labelled as 'out of scope' or coded 'different' for a given reference recommendation was not considered for the analyses of the rate of concordance as this indicated an absence of recommendation instead of concordance of recommendation. The reference recommendation was included for the calculation of rate of concordance only if ≥ 2 CPGs from Southeast Asia were coded as 'for' , 'against' , or 'insufficient' for a given reference recommendation.
For assessments of rate of concordance, the included CPGs were considered to be concordant with either the 2017 ACC/AHA guideline [22] or the 2018 ESC/ESH guideline [23] for a given reference recommendation if all comparator CPG codings were 'for' , or if all comparator CPG codings were 'for' or 'insufficient' but ≥ 60% were 'for' . On the other hand, the included CPGs was regarded as non-concordant with either the 2017 ACC/ AHA guideline [22] or the 2018 ESC/ESH guideline [23] for a given reference recomendation if any comparator CPG coding was 'for' and any other comparator CPG coding was 'against' , if comparator CPG codings were all either 'against' or 'insufficient' , or if all comparator CPG codings were 'for' or 'insufficient' but < 60% were 'for' .

Sensitivity analysis
Sensitivity analysis was conducted by the exclusion of 'insufficient' ratings from the analyses of rate of concordance. In addition, a leave-one-out sensitivity analysis was also performed to assess rates of concordance with the exclusion of each included CPG one at a time.

Characteristics of included clinical practice guidelines
We identified six CPGs [30][31][32][33][34][35] that corresponded to our inclusion and exclusion criteria, each one of them originated from Thailand, Malaysia, Indonesia, Brunei, Singapore, and Vietnam. We have formally approached the relevant professional bodies of the remaining five countries (the Philippines, Laos, Cambodia, Myanmar, and Timor Leste), but we were told that they did not produce CPGs for the management of hypertension at the time of conducting this study. Table 1 displays the characteristics of the included CPGs originated from Southeast Asia [30][31][32][33][34][35]. All the included CPGs [30][31][32][33][34][35] were published within the last five years (2017-2020). Except for the two CPGs originated from Malaysia [30] and Singapore [32] respectively which were developed by governmental institution, the remaining four CPGs [31,[33][34][35] were either developed by cardiovascular specialty societies or through joint collaboration of governmental institution and cardiovascular specialty societies.

Generation of reference recommendations
A total of 59 reference recommendations with unique and unambiguous P-I-C specifications was generated from the 2017 ACC/AHA guideline [22]. In addition, a total of 51 reference recommendations with unique and unambiguous P-I-C specifications was generated from the 2018 ESC/ESH guideline [23]. Table 2 depicts the P-I-C specifications of the reference recommendations from the 2017 ACC/AHA guideline (starts with the code ACC) and the 2018 ESC/ESH guideline (starts with the code ESC), respectively. These reference recommendations can be classified into seven different sections: "blood pressure measurement" (ACC-1; ESC-1), "diagnosis of hypertension" (ACC-2 to ACC-6; ESC-2 to ESC-5), "investigations in patients with hypertension" (ACC-7 to ACC-17; ESC-6 to ESC-15), "lifestyle modifications" (ACC-18 to ACC-23; ESC-16 to ESC-21), "goal blood pressure" (ACC-24 to ACC-31; ESC-22 to ESC-28), "pharmacotherapy for patients with hypertension and no comorbidity" (ACC-32 to ACC-41; ESC-29 to ESC-38), and "pharmacotherapy for patients with hypertension and comorbidity" (ACC-42 to ACC-59; ESC-39 to ESC-51). Full descriptions of the 59 reference recommendations generated from the 2017 ACC/AHA guideline and the 51 reference recommendations generated from the 2018 ESC/ESH guideline can be found in the supplementary files (Additional file 1: Table S1).

Concordance of recommendations for the management of hypertension with 2017 ACC/AHA guideline
Considering the six included CPGs from Southeast Asia [30][31][32][33][34][35], concordance was observed for 30 reference recommendations (50.8%) out of 59 reference recommendations generated from the 2017 ACC/AHA guideline [22] (Table 3). The codings of reference recommendations generated from the 2017 ACC/AHA guideline can be found in the supplementary files (Additional file 1: Table S2). Full concordance (100%) was observed for reference recommendations in the section of "blood pressure measurement" (n = 1/1) and in the section of "lifestyle modifications" (n = 6/6) ( Table 4). Concordance of reference recommendations in the section of "pharmacotherapy for patients with hypertension and no comorbidity" (n = 6/10) and in the section of "pharmacotherapy for patients with hypertension and comorbidity" (n = 12/18) achieved rates of 60.0% and 66.7%, respectively. Reference recommendations in the remaining sections achieved less than half concordance (50%): 20.0% (n = 1/5) in the section of "diagnosis of hypertension" and 36.3% (n = 4/11) in the section of "investigations in patients with hypertension". Complete non-concordance (0%) was reported for the reference recommendations in the section of "goal blood pressure" (n = 0/8) ( Table 4).

Concordance of recommendations for the management of hypertension with 2018 ESC/ESH guideline
Considering the six included CPGs from Southeast Asia [30][31][32][33][34][35], concordance was observed for 31 reference recommendations (69.8%) out of 51 reference recommendations derived from the 2018 ESC/ESH guideline [23] (Table 3). The codings of reference recommendations generated from the 2018 ESC/ESH guideline can be found in the supplementary files (Additional file 1: Table S3). Reference recommendations in the section of "blood pressure measurement" (n = 1/1) and in the section of "lifestyle modifications" (n = 6/6) achieved full concordance (100%) ( Table 4). This was followed by concordance in the reference recommendations consist in the section of "pharmacotherapy for patients with hypertension and comorbidity" (n = 11/13), in the section of "diagnosis of hypertension" (n = 3/4), and in the section on "pharmacotherapy for patients with hypertension and no comorbidity" (n = 6/10), which achieved rates of 84.6%, 75.0%, and 60.0%, respectively (Table 4). Reference recommendations in the remaining sections achieved less than half concordance (50%): 40.0% (n = 4/10) in the section of "investigations in patients with hypertension" and 0% (n = 0/7) in the section of "goal blood pressure" (Table 4).

Sensitivity analysis excluding insufficient ratings
There was no substantial change in the rate of concordance when "insufficient" ratings were removed from consideration in the sensitivity analysis (Table 3, Additional   file 1: Table S2, and Table S3). Since four reference recommendations (ACC-48, ACC-49, ACC-56, and ACC-57) in the 2017 ACC/AHA guideline [22] and two reference recommendations (ESC-49, and ESC-50) in   the 2018 ESC/ESH guideline [23], respectively, were with insufficient ratings for all of the six included CPGs, only 55 reference recommendations from the 2017 ACC/AHA guideline and 49 reference recommendations from the 2018 ESC/ESH guideline were considered in this sensitivity analysis. Across the six included CPGs [95-100], concordance was found for 33 reference recommendations (60.0%) out of 55 reference recommendations identified from the 2017 ACC/AHA guideline [26]. Whereas concordance was found for 32 reference recommendations (65.3%) out of 49 reference recommendations identified from the 2018 ESC/ESH guideline [27].

Leave-one-out sensitivity analysis
The findings from the leave-one-out sensitivity analyses indicated that no single CPG could explain the nonconcordance of recommendations (Table 3, Additional file 1: Table S4, and Table S5). The rate of concordance of recommendations in the 2017 ACC/AHA guideline [22] changed by an absolute of 0% (with the removal of either the CPG originated from Malaysia [30]
Other sources of non-concordance in recommendations were in the section of "pharmacotherapy for patients with hypertension and comorbidity" (six out of 18 recommendations were non-concordant; Table 4). Included CPGs were non-concordant for the recommendation in the 2017 ACC/AHA guideline [22] to prescribe thiazide diuretics or calcium channel blockers as equally preferred option as angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) for first-line therapy in adults with hypertension and chronic kidney disease but without moderately increased albuminuria (ACC-46). Other non-concordant recommendations in this section either turned concordant (n = 1; ACC-59) or were no longer in consideration (n = 4; ACC-48, ACC-49, ACC-54, ACC-55) once "insufficient" ratings were removed in the sensitivity analyses.
Other sources of non-concordance in recommendations were in the section of "pharmacotherapy for patients with hypertension and no comorbidity" (n = 4) which included the recomendations of thiazide diuretics (ESC-29 and ESC-30) and beta-blocker (ESC-37) as an option for first-line therapy, as well as the recommendation of thiazide diuretics, ACE inhibitors, ARBs, or calcium channel blockers being preferred over beta-blockers as an option for first-line therapy (ESC-38), in adults with hypertension but with no comorbidity requiring initial pharmacotherapy.

Discussion
It was encouraging to observe the concordance of the recommendations for proper blood pressure measurement and lifestyle modifications across the CPGs for the management of hypertension in Southeast Asia [30][31][32][33][34][35] with the 2017 ACC/AHA guideline [22] and the 2018 ESC/ESH guideline [23]. Accurate measurement and recording of blood pressure are of utmost importance in order to accurately classify the level of blood pressure, to guide management of hypertension, and to ascertain blood-pressure-related cardiovascular risk [22]. Although measurement of blood pressure in the office settings is relatively easy, it is not redundant for the emphasis in the CPGs for proper techniques of measurement, since in real-world clinical practice, it is often performed without adequate attention to the specified preconditions required for a valid measurement, which could lead to misestimation of patients' true level of blood pressure and prescription of unnecessary treatment [22,23]. On the other hand, nonpharmacological lifestyle interventions are effective in lowering blood pressure for patients with hypertension, with the most important approaches being weight loss, sodium reduction, increased physical activity, increased consumption of vegetables and fruits, reduction in alcohol consumption, and smoking cessation [22,23]. The recommendations of these lifestyle interventions were consistent across CPGs for the management of hypertension in Southeast Asia [30][31][32][33][34][35], and thus complete concordance with the 2017 ACC/AHA guideline [22] and the 2018 ESC/ESH guideline [23].
The blood pressure targets for patients with hypertension had always been controversial since the publication of the 2017 ACC/AHA guideline [22] which issued a groundbreaking recommendation that the goal blood pressure for most of the patients with hypertension should be < 130/80 mm Hg, including those without comorbidity. However, the 2018 ESC/ESH guideline [23] did not concur with the 2017 ACC/AHA guideline where a primary goal blood pressure of < 140/90 mm Hg was still recommended for all patients with hypertension but without comorbidity. Likewise, the recommended blood pressure target for patients with hypertension but without comorbidity was divided across the CPGs for the management of hypertension in Southeast Asia. Specifically, the CPGs originated from Malaysia [30], Brunei [31], and Singapore [32] respectively, were concordant with the 2018 ESC/ESH guideline [27], and the CPGs originated from Thailand [33], Indonesia [34], and Vietnam [35] respectively, were concordant with the 2017 ACC/AHA guideline [22], on the goal blood pressure for patients with hypertension age 18-60 years without comorbidity. None of the CPGs for the management of hypertension in Southeast Asia [30][31][32][33][34][35] was concordant with the 2017 ACC/AHA guideline [22] on the goal blood pressure (< 130/80 mm Hg) for patients with hypertension age > 60 years but without comorbidity, but the CPGs originated from Malaysia [30], Brunei [31], Singapore [32], and Thailand [33], respectively, were concordant with the 2018 ESC/ESH guideline [23] on the goal blood pressure (< 140/90 mm Hg) for patients with hypertension age 60-80 years but without comorbidity. CPGs originated from Indonesia [34] and Vietnam [35] respectively, advocated different blood pressure targets (< 140/80 mm Hg) than that specified in either the 2017 ACC/AHA guideline [22] or the 2018 ESC/ESH guideline [23]. Nonetheless, these CPGs from Southeast Asia [30][31][32][33][34][35] did not provide the rationale as to their recommended blood pressure targets in these patient populations.
Undeniably, the totality of the existing evidence in patients with hypertension indicates a reduction in the risk of major cardiovascular events and cardiovascular mortality with more intensive blood pressure lowering relative to standard blood pressure lowering. Specifically, the systematic review and meta-analysis (n = 23,169) [36] performed to inform the 2017 ACC/AHA guideline [22], which included randomized controlled trials with a systolic blood pressure target of < 130 mm Hg compared with any higher systolic blood pressure target reported significant risk reduction for stroke (relative risk = 0.82; 95% CI 0.70-0.96) and major cardiovascular events (relative risk = 0.84; 95% confidence interval 0.73-0.99). Similarly, another meta-analysis [37] of all available randomized controlled trials (n = 613,815) which had been cited in the 2018 ESC/ESH guideline [23] observed that further reduction per 10 mm Hg in systolic blood pressure reduced the rate of major cardiovascular events and death, even in patients with baseline systolic blood pressure between 130 and 139 mm Hg, indicating benefit at achieved systolic blood pressure of < 130 mm Hg. However, a meta-analysis of randomized trials (n = 255,70) [38] also reported that permanent discontinuation of drug therapy owing to adverse effects was significantly higher in patients with hypertension who had been targeted to achieve lower blood pressure. Therefore, advocating more intensive blood pressure lowering has to be considered alongside the accompanying risk of treatment discontinuation due to adverse events, which may counterweigh the limited incremental risk reduction of major cardiovascular events, and such consideration was the rationale that the 2018 ESC/ESH guideline [23] still recommended a primary blood pressure target of < 140/90 mm Hg. The recommendations of goal blood pressure across the included CPGs of Southeast Asia [30][31][32][33][34][35] most probably did not consider the cost-effectiveness of different goals blood pressure; in order to better inform the clinical practice, the CPG developer groups should conduct local cost-effectiveness analyses to determine if more intensive blood pressure lowering relative to standard blood pressure lowering is cost-effective, to balance between potential cost saving associated with an incremental reduction in major cardiovascular events and additional cost that would be spent for clinical care used to maintain lower blood pressure, including treatment for adverse events.
CPGs for the management of hypertension in Southeast Asia [30][31][32][33][34][35] were concordant with the recommendations in both the 2017 ACC/AHA guideline [26] and the 2018 ESC/ESH guideline [27] that ACE inhibitors, ARBs, and calcium channel blockers as the options for initial first-line therapy for patients with hypertension and no comorbidity. These three classes of antihypertensive agents have proven ability to reduce blood pressure and cardiovascular events, with broad equivalence on the risk reduction of overall cardiovascular morbidity and mortality in meta-analyses [37,39]. However, CPGs for the management of hypertension in Southeast Asia [30][31][32][33][34][35] were non-concordant with the recommendation of thiazide diuretics as an option for first-line therapy in the said population as specified in both the 2017 ACC/AHA guideline [22] and the 2018 ESC/ESH guideline [23]. The non-concordance was stemmed from the CPG originated from Brunei [31] which did not consider thiazide diuretics as an option for first-line therapy without rationale provided for their exclusion (thiazide diuretics as an option for second-line therapy); the remaining CPGs in Southeast Asia [30,[32][33][34][35] listed thiazide-type diuretics as one of the first-line options.
Nonetheless, a systematic review and meta-analysis (n = 247,006) [39] of head-to-head trials of various classes of antihypertensive agents found that the effects of all classes of antihypertensive agents (thiazide diuretics, calcium channel blockers, ACE inhibitors, and ARBs) were not significantly different on all evaluated outcomes, including the risks of stroke, cardiovascular disease, heart failure, cardiovascular death, and all-cause death, when their achieved blood pressure was equivalent. Indeed, thiazide diuretics were superior compared to all other classes of antihypertensive agents to reduce the risk of heart failure in patients with hypertension (relative risk = 0.83; 95% confidence interval 0.73-0.94) [39]. Likewise, the systematic review and meta-analysis (n = 152,379) [36] performed to inform the 2017 ACC/AHA guideline [22] which included head-to-head trials of different classes of antihypertensive agents reported that no other classes of antihypertensive agents (ie, calcium channel blockers, ACE inhibitors, and ARBs) were significantly better than thiazide diuretics as the first-line therapy for the following evaluated outcomes: thiazide diuretics were associated with a significantly lower risk for heart failure relative to calcium channel blockers; significantly lower risk for cardiovascular events and stroke relative to ACE inhibitors; and significantly lower risk for cardiovascular events relative to calcium channel blockers.
Whether beta-blockers should be included as one of the options for initial first-line therapy for patients with hypertension but without comorbidity is still debatable, with divided recommendations between the 2017 ACC/AHA guideline [22] and the 2018 ESC/ESH guideline [23]. The 2017 ACC/AHA guideline [22] did not include beta-blockers as one of the options for first-line therapy, which was followed suit in the CPGs originated from Brunei [31], Indonesia [34], and Vietnam [35], respectively; whereas the 2018 ESC/ESH guideline [23] included beta-blockers as one of the options for firstline therapy, which was followed suit in the CPGs originated from Malaysia [30], Singapore [32], and Thailand [33]. The CPG originated from Malaysia [30] particularly cited a 2017 systematic review [40] which reported that beta-blockers are effective in patients with hypertension < 60 years of age in terms of preventing death, stroke, or myocardial infarction (versus placebo and other antihypertensive agents) and thus they are highly reasonable first-line options in the treatment of hypertension for this population, although the CPG originated from Malaysia [30] itself did not specify the age of patients which beta-blockers should be listed as one of the first-line options. The CPG originated from Thailand [33] though acknowledged that beta-blockers may be inferior to other antihypertensive agents to reduce the risk of cardiovascular diseases, beta-blockers were still being listed as one of the options for first-line therapy due to their similar effects on blood pressure-lowering with other established first-line antihypertensive agents, including ACE inhibitors, ARBs, calcium channel blockers, and thiazide diuretics. The remaining CPGs in Southeast Asia [31,32,34, 35] did not provide a rationale for the inclusion or exclusion of beta-blockers as one of the options for first-line therapy.
The notion in the 2018 ESC/ESH guideline [23] that mortality and major cardiovascular outcomes were broadly similar with initial therapy using beta-blockers compared to other first-line antihypertensive agents including ACE inhibitors, ARBs, calcium channel blockers, and thiazide diuretics may not hold true with the currently available evidence. The meta-analysis [39] cited in the 2018 ESC/ESH guideline to justify the recommendation of beta-blockers as one of the initial first-line options for patients with hypertension but without comorbidity has been updated recently. The updated meta-analysis (n = 165,850) [41] which included hypertension trials reported significantly increased risks of stroke (relative risk = 1.21; 95% confidence interval 1.07-1.38), composite of stroke and cardiovascular diseases (relative risk = 1.09; 95% confidence interval 1.01-1.17), and all-cause mortality (relative risk = 1.06; 95% confidence interval 1.01-1.12) with beta-blockers as compared to other first-line antihypertensive agents. Nonetheless, although beta-blockers were listed as one of the options for first-line therapy in the 2018 ESC/ESH guideline, thiazide diuretics, ACE inhibitors, ARBs, and calcium channel blockers were being preferred over beta-blockers as first-line therapy for patients with uncomplicated hypertension [23].
The blood pressure cutoffs for the diagnosis of hypertension was perhaps the most robust debate in the domain of hypertension over the recent years; the 2017 ACC/AHA guideline [22] recommended diagnosis of hypertension based on the office (non-automated) systolic blood pressure reading of ≥ 130 mm Hg and/or diastolic blood pressure reading of ≥ 80 mm Hg, but the 2018 ESC/ESH guideline [23] did not follow suit and recommended the conventional cutoffs based on systolic blood pressure reading of ≥ 140 mm Hg and/ or diastolic blood pressure reading of ≥ 90 mm Hg. Interestingly, none of the CPGs for the management of hypertension in Southeast Asia [30][31][32][33][34][35] followed the cutoffs recommended in the 2017 ACC/AHA guideline [22], including those [30,31,[33][34][35] which are published later than the 2017 ACC/AHA guideline [22]; the conventional cutoffs (≥ 140/90 mm Hg) was still being recommended for practice. The developers of the CPG originated from Malaysia [30] believed that the new definition in the 2017 ACC/AHA guideline [22] would not change the way that patients with hypertension was treated, particularly those with cardiovascular complications and blood pressure of ≥ 130/80 mmHg who would need antihypertensive treatment regardless. In addition, the CPG originated from Vietnam [35] believed that the evidence was still insufficient to adopt the new definition recommended in the 2017 ACC/ AHA guideline [22].
The notion that the evidence was insufficient with regard to the new cutoffs for diagnosis of hypertension recommended by the 2017 ACC/AHA guideline [22] was probably true since it was merely based on meta-analyses [24,[42][43][44][45][46][47][48][49][50][51][52] of observational data. The 2017 ACC/ AHA guideline reviewed the available meta-analyses of observational studies [24,[42][43][44][45][46][47][48][49][50][51][52] and compared the reported hazards for cardiovascular events and stroke of different ranges of blood pressure with a blood pressure of < 120/80 mmHg: patients with a blood pressure of 120-129/80-84 mmHg was similarly at risk for cardiovascular events and stroke, with hazard ratios ranged between 1.1 to 1.5, compared to their counterparts with a blood pressure of 130-139/85-89 mmHg, with hazard ratios ranged between 1.5 to 2.0 [22]. However, the systematic review and meta-analysis [53] of randomized clinical trials with at least 1000 patient-years of follow-up cited in the 2018 ESC/ESH guideline [23] found significant risk reduction of death and cardiovascular events in patients with a baseline blood pressure of ≥ 140/90 mm Hg, while no observed benefits with lower baseline blood pressure. Therefore, it may be prudent to observe the impact in the management of hypertension in the United States of America with the new cutoff recommended in the 2017 ACC/AHA guideline [22] before the introduction of such cutoff in Southeast Asia. Despite not using the new cutoff proposed in the 2017 ACC/AHA guideline [22], all CPGs for the management of hypertension in Southeast Asia [30,31,[33][34][35], except the CPG