FormalPara Key Points

The burden of hypertension in Asia is high because of the large population base, the higher systolic/diastolic/mean arterial blood pressure (BP) in Asian versus Western individuals and the strong association between BP and stroke.

In general, calcium channel blockers are the most commonly prescribed antihypertensive agents in Asian countries, and in many, angiotensin receptor blockers are more commonly prescribed than angiotensin-converting enzyme inhibitors (ACEis), despite evidence suggesting that ACEis are associated with better cardiovascular outcomes; single-pill combinations are underutilised despite guideline recommendations, possibly because of availability and cost.

BP control rates are suboptimal, but tend to be higher in the more- versus less-developed Asian countries.

1 Introduction

The Asia-Pacific region is politically, economically and culturally diverse, making up 60% of the world’s population [1]. Even if the two most populous countries (China and India) were excluded, the Asia-Pacific region would still contain 1.5-fold more people than the European Union and North America combined [2].

Non-communicable diseases, such as cardiovascular disease (CVD), diabetes, cancer and chronic respiratory disease, are the leading causes of death globally and are largely preventable by modifying risk factors [3, 4]. High systolic blood pressure (SBP) is the leading global risk factor for death, accounting for an estimated 10.8 million deaths in 2019, and contributing to between 10 and 20% of the total burden of disability-adjusted life-years in most Asian countries [3]. Furthermore, hypertension is identified in numerous registries as the primary risk factor for stroke and cardiovascular disease [5]. This burden is recognised by the World Health Organization (WHO), with their aim of a 25% reduction in CVD by 2025 [6], as well as in guidelines advocating well-defined BP goals for patients without comorbidities (< 140/90 mmHg) and stricter targets for high-risk patients and those with known CVD (SBP of < 130 mmHg) [7].

While the published prevalence of diagnosed hypertension tends to be lower in Asian than in Western countries [8], the absolute number of people affected in Asia is considerably larger because of the population base [1]. Moreover, the relationship between BP and fatal/nonfatal stroke is stronger in Asian than in western populations [9]. Therefore, effective management of hypertension in Asia-Pacific is an important public health goal across a wide spectrum of healthcare scenarios (public health, primary care and hospital care).

The aim of the current article is to review the contemporary literature on hypertension management in Asia, focussing on rates of BP control, evidence for differential responses to antihypertensive drug classes in Asian patients and the role of renin–angiotensin–aldosterone system (RAAS) inhibitors (one of the treatments most commonly recommended by guidelines). We focus on five key research questions (see the Methods section) relevant to these issues. Our objective is to assess the issues to identify clinically relevant strategies and gaps in evidence required to improve BP control in the Asia-Pacific region.

2 Methods

For the purposes of this article, we have defined Asia-Pacific as the area bounded by Pakistan in the west, China in the north, Japan in the east and Indonesia in the south.

A literature search of the PubMed database was conducted to identify relevant English-language studies published between 1 January 2008 and 1 July 2022. Briefly, the search terms focussed on hypertension, RAAS inhibitor treatment, guidelines and the Asia-Pacific countries of interest (see Online Resource, Supplementary Table S1 for the complete literature search strategy).

The results of the literature search were supplemented with articles of interest from the bibliographic lists of identified articles, as well as from ad hoc literature searches that were undertaken to supplement these results.

To obtain information on these research questions, it was necessary to employ a proxy question so that more specific and objective data could be identified.

  • Q1. How are patients in the Asia-Pacific region different from rest-of-world patients? Proxy: Are there any biological, genetic or clinical characteristics distinguishing patients in the Asia-Pacific region from other ethnicities?

  • Q2. What are guideline recommendations regarding hypertension management in the Asia-Pacific region?

  • Q3: What is the role of RAAS inhibitors in clinical practice in the Asia-Pacific region? Proxy: What has been published on RAAS inhibitors in patients in countries in the Asia-Pacific region?

  • Q4: What real-world evidence is available on the pharmacological management of hypertension in the Asia-Pacific region? Proxy: What evidence exists to describe the treatment classes that are used in patients in the Asia-Pacific region?

  • Q5: Are patients in the Asia-Pacific region managed according to the guidelines in hypertension? Proxy: Are patients in the Asia-Pacific region managed to target BP levels/what are the control rates of hypertension?

In this article, the term ‘Korea’ is used to describe the Republic of Korea; no studies from the Democratic People’s Republic of Korea were identified. It should be noted that the literature search included studies published since 2008, while much of the data on angiotensin-converting enzyme inhibitors (ACEis) were published before this date. Consequently, additional citations have been included to provide a balanced description of both ACEis and angiotensin receptor blockers (ARBs).

3 Results

3.1 Literature Search

The literature search yielded 2537 articles of potential interest (see Online Resource, Supplementary Table S1). Titles and abstracts were reviewed, and articles were filtered by their relevance to the research questions.

After reviewing the results, appropriate articles were selected on the basis of geographic region, demographics, number of participants, timeframe of assessment, applicability and methodology. Of these, 100 were considered more suitable and full-text articles were acquired. After reviewing the full text for the 100 articles, 94 were considered relevant for inclusion. The relevant data from each of the 94 articles—as it relates to the research question—were identified and collated. The content of these articles—as well as ad hoc searching to supplement the information from these articles (where gaps existed) —were used to synthesise the following manuscript.

3.2 Q1. Characteristics of hypertension in individuals in the Asia-Pacific region

It is difficult to untangle the molecular/biological characteristics specific to Asian individuals when racial disparities in hypertension prevalence and control are potentially affected by environmental/social/cultural/economic factors, variable medication response/adherence and by the fact that risk stratification tools were developed in Caucasian populations [10, 11]. Emigration studies may provide some insight into genetic versus environmental determinants of hypertension within an ethnic group. However, studies of Asian people emigrating to the USA have noted that access to healthcare and insurance status are the most important determinants of BP diagnosis and control [10, 12].

3.2.1 Clinical Characteristics

Differences in the nature and outcomes of hypertension have been noted between Asia-Pacific and Western populations, including a higher likelihood of salt sensitivity among Asian versus Western individuals with hypertension and mild obesity [13], a higher incidence of stroke and non-ischemic heart failure in East Asian than Western populations [13], a high risk of CVD and metabolic diseases (e.g. type 2 diabetes) among people from South Asia (Indian subcontinent) [14] and a higher resting heart rate among patients in India [15, 16], Japan and Thailand [17].

A meta-analysis found that individuals of South Asian ethnicity have higher rates of stroke and CVD. Because the systolic and diastolic blood pressure were similar in the analysis, the authors suggested that the difference in stroke and CVD was driven by a higher prevalence of diabetes mellitus in South Asian populations [18]. However, a systematic review and meta-analysis by other researchers have reported that, compared with Europeans, South Asians have higher SBP, diastolic BP and mean arterial pressure, and the association between BP and stroke is stronger [19]. Compared with patients in the USA, Chinese patients had a lower prevalence of hypertension but higher average BP; severe elevated BP was 2.5 times more common in China [20]. This suggests that hypertension is underdiagnosed in China. Additionally, higher BP levels in Chinese and South Asians could contribute to the earlier onset of end-organ complications and a more challenging management path.

The circadian pattern of BP variation may also differ between Asia-Pacific and European individuals, with a higher prevalence of morning hypertension and night-time hypertension in Asian populations compared with European populations [21]. A systematic review of studies noted significant differences in BP measured at home in the morning or evening compared with BP measured in the clinic, with the difference between home-measured SBP and clinic SBP being significantly greater in Asian patients than European patients when measured in the evening. In contrast, the difference between home-measured SBP and clinic SBP was much larger (i.e. higher) in Europeans than Asians when measured in the morning [22].

Even within Asia-Pacific, there may be differences between countries in BP characteristics, for example, a comparison of ambulatory BP monitoring (ABPM) profiles between Japanese and Thai patients showed a higher 24-h and daytime BP and greater morning BP surge in Japanese patients, but a higher prevalence of riser status (higher night-time than daytime SBP) in the Thai population [17].

3.2.2 Genetic Differences

Multiple studies have identified genetic markers of hypertension in particular patient groups, but there are limited data identifying genotypes or haplotypes that are specific to certain races or that have a marked impact on response to antihypertensive therapy. Kato and colleagues identified single nucleotide polymorphism (SNP) coding for genes involved in vascular smooth muscle biology that were significantly associated with different BP parameters in European, South Asian (those from the Indian subcontinent) and East Asian individuals (see Online Resource, Supplementary Table S2 for the list of SNPs significantly associated with blood pressure parameters in European, South Asian and East Asian individuals), and showed clear differences between these ethnic groups [23].

Some genetic loci associated with hypertension may influence a differential response to particular types of treatment [24]. Studies in Asian patients with hypertension have identified associations with polymorphisms in a range of genes that may affect treatment response (Table 1) [25,26,27,28,29,30,31,32,33,34,35,36,37,38,39].

Table 1 Polymorphisms associated with hypertension in Asian individuals, and which may be related to treatment response
Full size table

However, reports on the actual impact of these polymorphisms on response to treatment are variable (see Online Resource, Supplementary Results) [37,38,39,40,41,42,43,44,45,46], precluding any clear conclusions.

Further research is needed to determine the relationship between genetic polymorphisms and treatment responses in Asian individuals with hypertension, as well as the differences in BP characteristics between North Asians (Chinese, Japanese, Koreans) and South Asians (Indians, Indonesians, Malaysians).

3.3 Q2. Asia-Pacific Hypertension Guidelines

To our knowledge, there is currently no unified Pan-Asian guideline for the management of hypertension, but such a unified guideline would streamline patient care and reduce heterogeneity in BP optimisation across the region. Several countries have national guidelines for the management of hypertension; those available in English are summarised in Table 2 [47,48,49,50,51,52,53,54,55,56,57,58,59,60]. Detailing the differences between Asia-Pacific guidelines and American College of Cardiology (ACC)/American Heart Association (AHA), European (European Society of Cardiology (ESC)/European Society of Hypertension (ESH)], and International Society of Hypertension (ISH) guidelines is beyond the scope of this review and has been comprehensively undertaken by Chia and colleagues in 2021 [61]. However, a brief overview is included below.

Table 2 Guidelines for the management of hypertension in Asia, where available, and the International Society of Hypertension guidelines. Threshold and target BPs refer to office-measured BP unless otherwise stated
Full size table

All Asia-Pacific guidelines provide three important BP levels to diagnose and manage hypertension: (1) threshold for diagnosis; (2) threshold for treatment; and (3) target BP. With the exception of Taiwan [55] and countries using the ACC/AHA guidelines (Bhutan, Laos, Myanmar and Nepal), Asia-Pacific guidelines define hypertension as office BP of ≥ 140/90 mmHg, and this is also a common threshold for active management of hypertension through lifestyle intervention and medication.

In six sets of Asia-Pacific guidelines, the general target BP during antihypertensive therapy is defined as < 140/90 mmHg [47,48,49,50,51, 54], with < 130/80 mmHg for high-risk patients in Brunei [47], China [49], Japan [54] and Korea [48]. However, guidelines from India [53], the Philippines [52] and Taiwan [55] define the target BP for most patients as < 130/80 mmHg, consistent with US recommendations [62].

With the exception of Brunei [47] and Taiwan [55], Asia-Pacific guidelines have a less stringent BP target for elderly patients (Table 2), but the age threshold for this target differs between guidelines, and is 60 years in India [53], 65 years in China [49] and Korea [48], 75 years in Japan [54] and 80 years in Malaysia [50], the Philippines [52] and Singapore [51]. Interestingly, these targets were mostly defined before publication of the STEP trial in China, which showed that cardiovascular outcomes are significantly reduced when elderly patients (60–80 years) are treated to a SBP target of 110–130 mmHg rather than a more lenient target of 130–150 mmHg [63]. The use of a higher BP target for elderly patients is usually due to concerns regarding adverse events; in the STEP study, however, hypotension was the only adverse event that occurred at higher rate in the group with the more stringent BP threshold (3.4% versus 2.6%; p = 0.03) [63]. The BP targets and definition of elderly patients appear to depend on social and cultural differences between the countries, with significant implications for treatment and levels of BP. In the primary prevention setting, there are also more aggressive targets for patients with type 2 diabetes and chronic kidney disease in guidelines from Brunei, China, Japan, Korea and Taiwan [47,48,49, 54, 55].

In patients without compelling indications, guidelines in Asia-Pacific countries consistently recommend an ACEi, ARB or a calcium channel blocker (CCB; usually a dihydropyridine), as first-line pharmacological therapy (Table 2) [47,48,49,50,51,52,53,54,55]. With the exception of guidelines from Brunei [47] and Pakistan [59], Asia-Pacific guidelines also include a diuretic (usually a thiazide or thiazide-like diuretic) ± a β-blocker among first-line options [48,49,50,51,52,53,54,55]. All except Cambodian guidelines [58] are consistent with the ISH 2020 guidelines in recommending initial combination therapy where office BP is markedly elevated. In most countries, this is defined as ≥ 160/100 mmHg [47,48,49,50, 53] but as > 150/100 mmHg in non-elderly people in the Philippines [52], ≥ 180/100 mmHg in Singapore [51] and > 20/10 mmHg above target in Taiwan [55]. Consistent with ISH guidelines [64], Korean, Philippine and Taiwanese national guidelines recommend a single-pill combination (SPC) versus a free combination to improve adherence and rates of BP control across the region [48, 52, 55]. The first-line recommendation is generally a RAAS inhibitor (ACEi or ARB) and CCB as a SPC, while SPC with a RAAS inhibitor and thiazide/thiazide-like diuretic are also frequently recommended.

3.4 Q3. Role of RAAS Inhibitors in Hypertension Management in Asia

Multiple studies in the literature search demonstrated that RAAS inhibition (achieved with both ACEi and ARBs) is effective in reducing BP in patients from South Asia (India, Pakistan), Northeast Asia (China, Korea, Japan) and Southeast Asia (Indonesia, Malaysia, the Philippines, Taiwan and Thailand), when used as monotherapy or as part of combination therapy [65,66,67,68,69,70,71,72,73,74,75,76].

The BP-lowering response to RAAS inhibitors in Asian patients is consistent with that observed in Western populations, but contrasts with African and African American cohorts, who exhibit an attenuated response [77]. This is particularly important in view of the high burden of vascular disease in the South Asian population and the vasoprotective effects of RAAS inhibitors [78].

A meta-analysis of studies in South Asian patients found that ACEis and ARBs were effective in reducing BP. Smaller BP reductions were found with other classes (Fig. 1) although the differences were not statistically significant [79]. In addition, in the large-scale ASCOT study, there was a significantly greater BP response with the addition of ACEi (perindopril) to CCB (amlodipine) in South Asian individuals than there was in patients of European or African origin [80]. An open-label study in patients in India showed significant BP reductions with ACEi/CCB/thiazide-like diuretic triple combination (perindopril/amlodipine/indapamide) in patients with moderate-to-severe hypertension inadequately controlled with two-drug therapy [73]. These data confirm that RAAS inhibitor-based therapy is effective in reducing BP in Asian patients.

Fig. 1
figure 1

Blood pressure reduction by drug class in South Asian individuals, according to a meta-analysis of 16 studies in 1719 patients with hypertension without a history of cardiovascular disease [duration of therapy 4 weeks to 9 months (median 8 weeks)] [79]. Data show mean [95% confidence intervals (CI)]. There were no significant differences between drug classes in the magnitude of blood pressure reduction. ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; CCBs, calcium channel blockers

Full size image

Both ARBs and ACEis have been shown to reduce cardiovascular outcomes in large-scale outcomes studies among patients with hypertension, including some with study centres in Asia-Pacific [81]. Reviews/meta-analyses have shown that ACEis reduce all cardiovascular endpoints, including all-cause mortality and stroke [81,82,83], whereas ARBs reduce most cardiovascular endpoints but do not appear to reduce the risk of all-cause mortality or MI [84].

A summary of the morbidity and mortality outcomes associated with ACEi and ARBs from studies with RAAS inhibitors is presented in Table 3 [85,86,87,88,89,90,91,92,93,94,95]. Only a few randomised controlled trials (RCTs) were identified with ACEi- or ARB-based regimens in Asia [94, 96], and few sub-analyses of a large RCT in Asian populations have been reported [86, 97]. For ACEi-based regimens, among 1650 Japanese patients with hypertension and coronary artery disease who received 3 years of treatment with either CCB (nifedipine retard) or ACEi (enalapril, imidapril or lisinopril), the incidence of cardiac events and mortality did not differ between groups [94]. In a study comparing the efficacy of CCB (amlodipine) and ACEi (lisinopril) in 120 patients with hypertension and microalbuminuria, lisinopril and amlodipine had comparable antihypertensive efficacy, but only lisinopril significantly reduced urinary albumin excretion [96]. Among patients with a history of cerebrovascular disease who received perindopril + indapamide in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, after a median follow-up of 3.9 years, BP reductions were greater among Asian participants than among Western participants [97]. A post hoc analysis of PROGRESS has shown that treatment with ACEi (perindopril) ± thiazide-like diuretic indapamide was associated with a significant reduction in the risk of total major vascular events among both Western and Asian patients but noted that there was a trend towards greater benefit in many clinical outcomes in Asian patients. However, the authors note that due to the limited study sample size, this trend was not definitive [86].

Table 3 Morbidity/mortality outcomes from randomised, prospective studies and real-world studies with RAAS inhibitors
Full size table

A large 5-year cohort study compared the efficacy of two types of ACEi—lisinopril and perindopril—on all-cause and CV-related mortality among 15,622 patients in Hong Kong. Compared with lisinopril, perindopril was associated with significantly lower all-cause mortality and CV-related mortality (both p < 0.05), an effect that was most significant among those older than 70 years, suggesting that intra-class variation might exist among ACEi in terms of mortality outcomes [93].

For ARB-based regimens, the HIJ-CREATE study examined whether ARB therapy (candesartan) can reduce the incidence of CV events compared with non-ARB-based standard pharmacotherapy in coronary artery disease (CAD) patients with hypertension in Japan. After a median follow-up of 4.2 years, candesartan showed no significant reduction in major adverse cardiovascular events (MACE), CV death, non-fatal myocardial infarction (MI) or heart failure compared with the non-ARB treatment group. However, new-onset diabetes and the incidence of drug discontinuation due to adverse events was significantly lower with candesartan than with non-ARB therapy [90].

Sub-analyses of some of the randomised, controlled large-scale ARB trials (ONTARGET, which compared telmisartan, ramipril and telmisartan + ramipril, and VALUE, which compared valsartan with amlodipine) showed no significant difference in efficacy outcomes by ethnicity or region [89, 95, 98, 99].

Similarly, in a prospective, randomised, open-label, blinded-endpoint Japanese study comparing the efficacy of an ARB (olmesartan) in combination with a CCB or diuretic among 2568 patients with hypertension, there was no significant difference in nonfatal cardiovascular events between treatment groups [92].

There are some real-world data on ethnic differences in response to RAAS inhibitors. An analysis of real-world data from eight international databases in Europe, the USA and Korea found consistent results in all regions: there was no significant difference in outcomes (acute MI, heart failure, stroke or CV events) between ARBs or ACEi when these agents were used as first-line treatment for hypertension [87].

Results from a few observational cohort studies in Korean patients with MI/CAD indicate that ACEis have greater benefit on CV mortality than ARBs [85, 88, 91, 100]. These studies are summarised in Table 3 and described in more detail in Online Resource, Supplementary Results.

When looking at safety and tolerability data, subgroup analyses from ONTARGET (ramipril, telmisartan or the combination) and TRANSCEND (telmisartan or placebo among patients at high risk of cardiac events who were intolerant to ACEis) studies indicate that Asian patients were more tolerant to treatment than the overall study population [89]. More Asian patients were able to achieve the full dose of either active drug, fewer Asian patients withdrew from the study and fewer Asian patients withdrew due to adverse events [89]. Similarly, in the aforementioned PROGRESS trial, after a median follow-up of 3.9 years Asian patients were more likely to persist with study treatments. The absolute rates of discontinuation among Asian patients were half that of Western patients (14% versus 29% versus for active treatment and 12% versus 26% for placebo) [97].

In the HIJ-CREATE study amongst patients with CAD and hypertension, over a median follow-up of 4.2 years, the most frequent adverse events with ARB-based therapy were dizziness (16.8%) and liver dysfunction (5.0%), while the most frequent events in the non-ARB group were cough (16.1%) and dizziness (15.0%) [90].

A network meta-analysis of studies in Asian patients found that each of the ARB + amlodipine combinations were similarly effective, and had tolerability profiles that were comparable to, or better than, amlodipine monotherapy [101]. Further data supporting the combination of an ARB + CCB come from a prospective, randomised, open-label blinded-endpoint Japanese study, which found that serious adverse events occurred less frequently in the ARB + CCB group than ARB + diuretic group [92].

Dry cough is a common side effect of ACEis, but the incidence may vary between individual ACEis [102]. Data from three studies in Indian patients, all with perindopril alone or in combination with amlodipine or indapamide, reported an ACEi-induced cough incidence in 0.4–4.3% of patients, consistent with global data [103,104,105].

More research is needed on the reduction of cardiovascular events or target organ damage (left ventricular hypertrophy, microalbuminuria and hypertensive retinopathy, etc.) in Asian patients and on differences between patients from different ethnic backgrounds in the region. More data are also needed to determine what the optimal antihypertensive regimen is for Asian patients with hypertension.

Two such sources of data may be the ongoing Treatment Optimization for Blood pressure with Single pill combinations in India (TOPSPIN) and Effects of intensive Systolic blood Pressure lowering treatment in reducing RIsk of vascular events (ESPRIT) trials. TOPSPIN is a randomised controlled study comparing 6-month treatment with three SPCs, each containing two antihypertensive agents (specifically, perindopril/amlodipine, perindopril/indapamide and amlodipine/indapamide) on 24-h ambulatory BP monitoring in 1968 patients with hypertension in India (https://clinicaltrials.gov/ct2/show/NCT05683301). ESPRIT is a randomised controlled study that will examine the incidence of major cardiovascular events in patients in an intensive treatment group (SBP target < 120 mmHg) compared with patients in a standard treatment group (SBP target < 140 mmHg) over 4 years of follow-up in China (https://clinicaltrials.gov/ct2/show/NCT04030234).

3.5 Q4. Treatment Patterns

Data on antihypertensive treatment patterns in Asia usually predate the most recent iteration of national guidelines, but notably, reported treatment patterns are generally consistent with guideline recommendations (Table 4) [106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129]. In general, CCBs were the most commonly prescribed antihypertensive agents (certainly in China, Hong Kong, Taiwan, Japan, India and Thailand), and this is consistent with an overall survey of physicians attending hypertension conferences/meetings who reported that CCBs are the most common treatment (China, Taiwan, Indonesia, Thailand, Vietnam, Myanmar, Pakistan, South Korea, Philippines, Malaysia, Egypt, Hong Kong, Saudi Arabia) [130].

Table 4 Most commonly prescribed classes of antihypertensive medication in Asia (numbers indicate the rankings based on the proportion of patients receiving that therapy, where 1 = most commonly prescribed, 2 = second most commonly prescribed, etc.), from studies published between January 2008 and July 2022
Full size table

Prescription data on antihypertensive use in China were principally from hospital studies. CCBs and ARBs were the most common antihypertensive agents prescribed at 59 general hospitals in Beijing, Tianjin, Guangzhou and Hangzehn [127], as well as at community health centres across China (n = 249,830) [124] and a tertiary hospital in Wuhan City [128]. This pattern may in part reflect the findings of the large-scale FEVER study in China, which showed that the dihydropyridine CCB felodipine was effective in reducing cardiovascular events in Chinese patients with hypertension, as well as reducing BP [131]. For patients with hypertension and CAD (n = 286,155), β-blockers and CCBs were the most commonly prescribed treatments at a Beijing tertiary hospital [128].

CCBs were the most commonly prescribed antihypertensive agents, followed by β-blockers, in two analyses of the public primary care database in Hong Kong [115, 132]; however, in a more recent analysis that included primary, secondary and tertiary hospitals in addition to primary care, the most commonly prescribed agents were CCBs first, ARBs second, and β-blockers third [126].

CCBs and RAAS inhibitors (either ACEi or ARBs) were the most prescribed antihypertensive therapies in Taiwan, according to an analysis of the nationwide Longitudinal Health Database, which included 219,425 patients with hypertension [119].

Similarly, in Japan, CCBs are the most common followed by RAAS inhibitors (usually ARBs), while diuretics are commonly used in elderly patients [113, 114, 117, 121, 133]. The high use of CCBs in Japan was demonstrated in an analysis of pharmacies dispensing in Kitakyushu City (10,585 antihypertensive prescriptions) [113], a review of prescriptions dispensed at three Tokyo hospitals (n = 27,033 without diabetes and n = 4604 with diabetes) [117] and two nationwide medical insurance claims analyses (one n = 59,867 [114, 133] and the other n = 1,863,298 [121]).

An analysis of prescribing data from a national private healthcare database in India found that CCBs were the most commonly prescribed antihypertensives for monotherapy [123], and CCBs were also the most commonly prescribed for stage 2 hypertension according to a retrospective study of 2540 patients treated by 508 Indian cardiologists [122]. However, in a registry-based study of patients with resistant hypertension in India (n = 3073), CCBs were the second most commonly used antihypertensive agents after β-blockers [110]. Combined therapy is the most common treatment approach in India (double, triple, quadruple and quintuple therapy), followed by monotherapy with CCBs, β-blockers, and ARBs [110, 122, 123].

In a cross-sectional survey among 2007 outpatients with hypertension in Thailand, there was an almost even distribution across CCBs (49%), diuretics (45%) and β-blockers (44%) [106].

Countries where CCBs were not the most commonly prescribed agents were Korea [118], Indonesia [129], Pakistan [112] and Vietnam [107]. In Korea, an analysis of the national health insurance claims database reported that ARBs were the most commonly prescribed antihypertensives, both as monotherapy and in combination [118], with > 50% of patients receiving combination therapy [134]. ACEis were also the most commonly prescribed antihypertensive agents in an analysis of prescribing at a hospital in Vietnam (n = 388) [107], whereas in Pakistan, ACEis were the second most common class of antihypertensives after β-blockers, according to a survey of general practitioners (n = 58) and hospital physicians (n = 42) in Karachi [112].

In most studies, the majority of hypertensive patients received combination therapy [106, 110, 113, 114, 118, 122,123,124, 135, 136]. The most common combinations in Japan were ARB + CCB or ARB + diuretic [113, 133]. An analysis of healthcare insurance claims in Japan found that, when patients required additional BP-lowering on ARB monotherapy (n = 75,811), the most common add-on treatment was a CCB and the second most common a diuretic [111].

At community health centres in China, the most common combination for hypertension was a diuretic + centrally acting drug [124], whereas for patients with CAD + hypertension treated at a Beijing tertiary hospital, combination therapy most commonly included a β-blocker, a CCB, an ARB or a diuretic (in that order) [128]. In Indonesia, the most common combination was a CCB + ARB in all age groups [129].

SPC use as a proportion of all antihypertensives was 0.1% in China [126], 5% in Thailand [106], 39.1% in India [123] and 55.3% in Korea [118]; in Japan, 26% of patients who received combination antihypertensive therapy received an SPC [133].

While these data provide insight into the common treatments used, it is difficult to know the extent to which treatment patterns in Asia are influenced by comorbidities or compelling indications, since some types of antihypertensives are recommended for patients with certain conditions, for example, RAAS blockers in chronic kidney disease (CKD), β-blockers in heart failure or angina and CCBs in CAD or chronic obstructive pulmonary disease. Similarly, treatment patterns will be highly influenced by financial factors, including disparities in national gross domestic product (GDP) between countries and the mechanism by which antihypertensives are funded.

3.6 Q5. Rates of BP Control

The studies in our literature search were heterogeneous in terms of BP control with different BP goals, and did not necessarily use guideline-recommended targets. Studies published between 2008 and 2022 reported nationwide rates of BP control among treated individuals of between 3.8% (in Nepal) and 73.0% (in Korea; Online Resource, Supplementary Table S3) [137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157].

It is difficult to compare rates between countries because of differences in study designs, patient eligibility criteria, definitions of BP control, urban versus rural populations, healthcare systems and national guideline recommendations on BP targets. Despite this, there was a general trend towards better BP control with higher Human Development Index (HDI) ranking (see Fig. 2; and Online Resource, Supplementary Table S4 for the HDI ranking of Asian countries). Where trends over time were available, they showed that BP control rates are improving [137, 142, 143, 157].

Fig. 2
figure 2

Blood pressure (BP) control rates as a function of Human Development Index (HDI) ranking (2018) [137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157]. See Online Resource Supplementary Table S3 for information about BP control rates in individual studies and Supplementary Table S4 for HDI rankings

Full size image

Several factors may influence rates of BP control in clinical practice, including patient adherence (which itself may be influenced by the asymptomatic nature of hypertension and/or fear of side effects), the use of alternative therapies, drug cost/reimbursement, and access to healthcare. Not all these factors have been studied, but our search did identify some studies showing better BP control among certain subgroups of patients (Table 5). Nonmodifiable factors that influenced BP control included sex/gender [137, 139,140,141, 145, 146, 149, 150, 153, 158], ethnicity [137, 144, 145, 154], age [137, 141, 142, 144, 149, 154, 158], family history [154], time since diagnosis [139] and the presence of cardiovascular disease [159] or comorbidities [143, 145]. Socio-economic factors that affected BP control included living in an urban versus rural area [137, 138, 146, 154], household income [139, 141, 144,145,146, 149, 150], education level [141, 144, 145, 150, 154], marital status [145, 146, 149, 150], employment status [144, 146] and health insurance [139]. On the other hand, there was no difference in BP control based on education, area of residence or income in Indonesia [140].

Table 5 Factors significantly associated with improved blood pressure control in Asia
Full size table

Modifiable factors associated with better BP control were receipt of monotherapy compared with ≥ 2 antihypertensive therapies [145], compliance with treatment [148], a body mass index (BMI) in the low or normal range [137, 149, 154, 159] (although control was better with higher BMI in Bangladesh [150]), having a balanced diet [159] and being physically active versus sedentary [158].

BP control also differed by region within some countries, including Bangladesh [150], Cambodia [139], China [145] and India [149].

4 Discussion

Although Asia-Pacific is the most populous region in the world, much of the data on hypertension management have been extrapolated from non-Asian patients, and there are important gaps in our knowledge regarding the applicability of these data to clinical practice in the Asia-Pacific region. The demographic and clinical characteristics of Asia-Pacific patients with hypertension do differ from those in the West, with the former having generally smaller BMI, higher rates of smoking, lower rates of alcohol consumption, higher incidence of previous stroke and a lower incidence of pre-existing CVD [160]. Data suggest that patients with hypertension in resource-limited settings are more likely to have end-organ damage compared with those in resource-rich settings [161], but there are limited data on this from Asia-Pacific. In addition, there are likely genetic variants related to hypertension development and treatment response that differ between patients in Asia-Pacific and Western populations, but more research is needed to define the clinical implications of such differences.

While most countries in the Asia-Pacific region have national guidelines, there is no regional Asia-Pacific hypertension guideline, even though there are consensus documents for other noncommunicable diseases, such as diabetes and dyslipidaemia [162, 163]. There is also some variability between the guidelines in Asia-Pacific, with not all local guidelines conforming to international guidelines, such as those from ISH (Table 2).

There is also a gap between the recommendations in national guidelines and their implementation in real-world clinical practice. Golestaneh and colleagues identified a number of barriers to guideline implementation in resource-limited settings, including: (1) length and complexity of guidelines (brief, simplified guidelines were preferred); (2) access to international guidelines, particularly for physicians with English as a second language; (3) trust in guidelines (physicians had greater trust in the quality of international than local guidelines); (4) perceived lack of relevance of the guidelines for certain patient groups (e.g. very young patients, those with multiple comorbidities or taking multiple medications, patients with resistant hypertension or target organ damage); (5) patients’ health literacy and ability to make lifestyle changes; (6) availability and affordability of recommended treatments; (7) lack of access to resources such as BP monitors, diagnostic services for target organ damage; and (8) patient’s ability to afford and/or travel to access services [164]. Many of these issues are present in Asia-Pacific, including lack of infrastructure (e.g. general practice databases) or networking between centres (public and private) and variable health insurance programs/drug reimbursement.

There are also insufficient data to know whether countries are in fact meeting the guideline targets. Our literature search did not identify any nationwide analyses of BP control rates, and all of the studies we identified used a single BP threshold to define BP control, rather than guideline-defined targets, which often differ by age and concomitant conditions. Without data from audits of national databases, the only way to evaluate BP control rates is to rely on the studies reported in the literature, which differ in their design and patient populations.

RAAS inhibitors (ACEis/ARBs) are a major class of therapy both alone and in combination and are included as a first-line therapy recommendation in all international and Asia-Pacific national guidelines for hypertension [47,48,49,50,51,52,53,54,55,56,57,58,59,60]. They have been shown to be effective and safe antihypertensives for reducing BP and improving outcomes in Asian populations [63, 65,66,67,68,69,70,71,72,73,74,75,76, 89, 95, 98, 99, 101].

Adherence is a major challenge in Asian populations. For this reason, SPCs are also given high priority in the national guidelines because they simplify therapy and improve adherence. Access to treatment and availability of affordable SPCs could help improve BP control rates in the Asia-Pacific region, and pharmacoeconomic analyses demonstrating their cost-effectiveness in the region would support reimbursement decisions. Greater availability of dual combinations containing a RAAS inhibitor with a CCB or thiazide or thiazide-like diuretic is preferable, so that a simple triple combination can be prescribed when dual therapy fails.

There is a clear need for more research to produce high-quality long-term data on the effect of RAAS inhibitors on cardiovascular outcomes in hypertensive patients in Asia-Pacific. This could include Asian subpopulations of large-scale randomised controlled trials—of which there is a dearth (see Online Resource, Supplementary Table S5)—but should also include real-world studies of patients in the region. There is an inherent limitation in extrapolating results from migrant Asian populations in Western countries to native Asians.

The literature on antihypertensive treatment patterns in Asia-Pacific suggests that CCBs are most commonly prescribed, as monotherapy or part of combination, and that—with the exception of India—there are low rates of SPC usage. CCBs are likely to be popular due to the ease of use and low cost of treatment, perceived low risk of adverse effects (oedema and constipation are rare) and low requirement for immediate patient follow-up. SPC use appears to be low, despite the fact that combination therapy is a recommended first-line treatment approach that produces more rapid reduction in BP compared with monotherapy [165]. However, on the basis of the age of the usage studies identified in our literature search, these studies may not reflect current usage patterns.

Poor and highly variable BP control rates are seen in most Asia-Pacific populations, with wide variability between and within countries. A unified guideline across Asia-Pacific may contribute towards better detection, treatment and control of hypertension, and would be easier to update as newer treatments and management strategies become available. However, such a guideline needs to have a clear and uncomplicated message with an easy-to-follow algorithm to make it easy to implement in a range of settings, including resource-limited settings and by physicians whose first language is not English [164].

Our review is not without limitations. To produce a manageable number of results, it was necessary to restrict the date range of the literature search to between 2008 and 2022. In addition, our search strategy required that the country term appeared in the title of the article (if the country term was searched in the title or abstract, this yielded an unmanageable number of results). Similarly, we searched only PubMed, so our analysis does not include potentially relevant studies that were not published in PubMed-indexed journals, such as regional/national journals.

Other limitations are the difficulties in drawing definitive conclusions because of the variability in the methodology and quality of the studies from the Asia-Pacific region. Efforts were made to include as many countries as possible, but this also meant including some studies with smaller samples/less rigorous data acquisition.

4.1 Strategies to Improve BP Control in Asia-Pacific and Recommendations for Future Research

On the basis of our review of regional hypertension management, several recommendations on strategies to improve BP control in Asia-Pacific and future research priorities can be made.

An important step in improving BP control in the Asia-Pacific region is greater awareness and treatment. Unfortunately, less than two-thirds of patients with hypertension in Asia are aware of their condition [137,138,139,140,141, 143, 145,146,147, 149,150,151,152,153,154,155,156,157,158]. Initiatives such as May Measurement Month (MMM), a global program by ISH and the World Hypertension League, are important in raising awareness and diagnosis [166]. Data from the 2019 MMM indicate that 46.2% of hypertensive individuals in South Asia and 57.9% in East Asia were aware of their diagnosis [167]. Home BP monitoring is also very useful for confirming the diagnosis of hypertension, with greater sensitivity and specificity than office-based measurement [168], but is not universally available and must be tailored to the social/cultural circumstances of the patient.

Once hypertension has been diagnosed, physicians in Asia-Pacific need to ensure that patients are treated to achieve target BP, and not just to achieve lower BP, since time at target BP is an important determinant of cardiovascular outcomes [169]. A simple unified Asia-Pacific guideline for hypertension management may help improve BP control, particularly if the guideline considers the potential barriers to guideline implementation described above [164]. Such a guideline may be particularly helpful in small and/or resource-limited countries, where the cost/time required for national guideline development may be prohibitive.

Most patients with hypertension can achieve target BP with treatment; the prevalence of resistant hypertension (i.e. elevated BP despite treatment with ≥ 3 antihypertensive agents) is low, affecting ~ 10% of patients in Asia-Pacific [170, 171]. However, therapeutic inertia (failure to initiate and intensify treatment when the patient is not at goal BP) is more common, including in the Asia-Pacific region [172,173,174]. Data from the HAPPEN study in China indicated that physicians generally overestimate the proportion of hypertensive patients who achieve BP control and are satisfied with their patients’ level of BP control. The reasons physicians gave for patients not achieving target BP were that the medication had not had enough time to work, the patient was nonadherent or experiencing side effects, the initial dose was too low, comorbidities or the patient’s lack of understanding about hypertension [175].

Another key step towards improving outcomes in Asia-Pacific patients is to improve adherence to therapy [176]. The rate of non-adherence to antihypertensive medication in Asia-Pacific is estimated to be 48%, with a higher rate of nonadherence in women than men, and in low- or lower-middle-income countries than in upper-middle- or high-income countries [177]. There are multiple potential barriers to adherence (Online Resource, Supplementary Table S6) [178]. While not all the barriers are modifiable, Devine and colleagues noted that physicians in the Asia-Pacific can minimise many of these barriers by building a trusting relationship with their patients and tailoring a treatment regimen to suit the patient’s lifestyle and financial situation [178].

Studies in Asia have demonstrated that both adherence and BP control can be improved through primary-care- or pharmacy-based initiatives. For example, a multicomponent primary care intervention in Singapore involving physician training in risk-based treatment of hypertension, nurse training in motivational conversations, telephone follow-up and subsidised SPC (losartan-hydrochlorothiazide) medication led to a significantly greater reduction in BP at 2 years versus usual care [179]. Similarly, a pharmacist-led program in China significantly improved short-term medication adherence, BP reductions and BP control, and led to timely medication adjustments by physicians [180].

With increasing adoption of digital technology in Asia, there is also potential to use telehealth (consultation and monitoring), mobile phone applications, wearable technologies and text messaging to positively influence antihypertensive adherence and BP control [181,182,183,184]. Although access to technology differs across the region, now is the ideal time to incorporate telemedicine and remote monitoring into hypertension management by building on the experience of clinical practice during the COVID-19 pandemic.

As described earlier, one of the factors associated with poor adherence is the number of medications the patient must take and the affordability of medications [185,186,187,188]. Use of a SPC instead of a free combination of antihypertensives is associated with improved adherence and BP control but may cost more than separate medications if not subsidised [189]. However, studies (including from China) show that SPCs are associated with lower overall costs over time because better adherence, persistence and BP control result in fewer major cardiovascular events, hospitalisations and specialist visits, and less time off work [190, 191].

5 Conclusions

Our review demonstrates that BP control in Asia-Pacific is suboptimal, and disproportionately so compared with Western nations. Whilst several aspects of pathophysiology and optimal management of hypertension in the Asia-Pacific region await elucidation, a unified Asia-Pacific guideline on hypertension management with pragmatic recommendations, particularly in resource-limited settings, is essential. RAAS inhibitors have been shown to be effective and safe for reducing BP and improving outcomes, but large outcome studies specifically in multi-national Asian populations are lacking. In clinical practice in Asian countries, ARBs are more often used than ACEis, despite the absence of recommendation from guidelines and clinical evidence supporting the preferential use of one over the other. Wider access and availability of affordable treatments, particularly SPCs, is needed, as well as effective public health screening programs to drive health-seeking behaviours among patients. Ideally, antihypertensive treatment should be tailored to the individual patient, but currently there are limited data on the characteristics of hypertension in Asia-Pacific individuals. Only through research can we develop the comprehensive approach to hypertension screening, diagnosis and treatment that is needed to optimise outcomes in the Asia-Pacific region.