research project on hypertension

• Open access
• Published: 01 May 2022

Interventions in hypertension: systematic review and meta-analysis of natural and quasi-experiments

• Tong Xia   ORCID: orcid.org/0000-0001-7136-8361 1 ,
• Fan Zhao   ORCID: orcid.org/0000-0002-1261-5841 1 &
• Roch A. Nianogo   ORCID: orcid.org/0000-0001-5932-6169 1 , 2  

Clinical Hypertension volume  28 , Article number:  13 ( 2022 ) Cite this article

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Hypertension is an urgent public health problem. Consistent summary from natural and quasi-experiments employed to evaluate interventions that aim at preventing or controlling hypertension is lacking in the current literature. This study aims to summarize the evidence from natural and quasi-experiments that evaluated interventions used to prevent or control hypertension.

We searched PubMed, Embase and Web of Science for natural and quasi-experiments evaluating interventions used to prevent hypertension, improve blood pressure control or reduce blood pressure levels from January 2008 to November 2018. Descriptions of studies and interventions were systematically summarized, and a meta-analysis was conducted.

Thirty studies were identified, and all used quasi-experimental designs including a difference-in-difference, a pre-post with a control group or a propensity score matching design. Education and counseling on lifestyle modifications such as promoting physical activity (PA), promoting a healthy diet and smoking cessation consultations could help prevent hypertension in healthy people. The use of computerized clinical practice guidelines by general practitioners, education and management of hypertension, the screening for cardiovascular disease (CVD) goals and referral could help improve hypertension control in patients with hypertension. The educating and counseling on PA and diet, the monitoring of patients’ metabolic factors and chronic diseases, the combination of education on lifestyles with management of hypertension, the screening for economic risk factors, medical needs, and CVD risk factors and referral all could help reduce blood pressure. In the meta-analysis, the largest reduction in blood pressure was seen for interventions which combined education, counseling and management strategies: weighted mean difference in systolic blood pressure was − 5.34 mmHg (95% confidence interval [CI], − 7.35 to − 3.33) and in diastolic blood pressure was − 3.23 mmHg (95% CI, − 5.51 to − 0.96).

Conclusions

Interventions that used education and counseling strategies; those that used management strategies; those that used combined education, counseling and management strategies and those that used screening and referral strategies were beneficial in preventing, controlling hypertension and reducing blood pressure levels. The combination of education, counseling and management strategies appeared to be the most beneficial intervention to reduce blood pressure levels.

Cardiovascular diseases (CVD) represent the leading cause of death, accounting for one in three deaths in the United States (US) and worldwide [ 1 , 2 , 3 ]. One of their most potent risk factors, hypertension (also known as high blood pressure), is a common risk factor for CVD [ 3 , 4 ]. Approximately 40% of adults aged 25 and over had elevated blood pressure in 2008 [ 3 ]. What is more, hypertension is responsible for at least 45% of deaths due to heart diseases and 51% of deaths due to stroke worldwide [ 3 , 4 ]. In the US alone, the direct medical and indirect expenses from CVDs were estimated at approximately $329 billion in 2013 to 2014 [ 5 ]. Effective large-scale interventions to prevent or treat hypertension are therefore urgently needed to reverse this trend. Yet, as new and promising interventions are surfacing every day, the need for rigorous evaluation of these interventions to inform evidence-based policies and clinical practice is ever growing.

To this effect, several randomized clinical trials (RCT) have been conducted to evaluate interventions used to prevent hypertension or improve its control [ 6 , 7 , 8 ]. However, although RCTs represent the gold standard for evaluating the efficacy (i.e., impact under ideal conditions) of most health interventions because of their high internal validity [ 9 , 10 ], they are not always feasible, appropriate or ethical for the evaluation of certain types of interventions. Furthermore, results from RCTs are not always generalizable to populations or settings of interest due to the highly selected sample and because the intervention is generally conducted under more stringent conditions ( low external validity ) [ 11 ]. To evaluate the effectiveness of an intervention (i.e., impact under real conditions) and to increase the uptake and implementation of evidence-based health interventions in the communities of interests, other types of experimental designs have been proposed. One such example is natural and quasi-experiments. The terms “natural experiments” and “quasi-experiments” are sometimes used interchangeably. In this study, and as described by others [ 12 ], we will distinguish these two concepts. Natural and quasi-experiments are similar in that, in both cases, there is no randomization of treatments or exposures (i.e., no random assignment). They differ, however, in that, natural experiments are those that involve naturally occurring or unplanned events (e.g., a national policy, new law), while quasi-experiments involve intentional or planned interventions implemented (typically for the purpose of research/evaluation) to change a specific outcome of interest (e.g., a community intervention program). Furthermore, in natural experiments, the investigator does not have control over the treatment assignment whereas in quasi-experiments, the investigator has control over the treatment assignment [ 12 ]. These experiments include difference-in-difference (DID) designs, synthetic controls and regression discontinuity designs to name a few [ 13 , 14 , 15 ].

As utilization of natural and quasi-experiments is increasing in public health and in the biomedical field [ 13 , 14 , 15 ], more natural and quasi-experiments are being conducted to evaluate interventions targeted to prevent or control hypertension [ 16 , 17 , 18 , 19 ]. This could be due to recent development or the reframing of classical approaches for determining causality in natural and quasi- experiments [ 13 , 14 , 15 , 20 ]. However, unlike RCTs of interventions aiming to prevent hypertension or improve its control [ 6 , 7 , 8 ], consistent summary and synthesis of evidence from natural and quasi- experiments is lacking in the current literature. The primary aim of the current systematic review is to summarize the evidence from natural and quasi-experiments that have evaluated interventions used to prevent, control hypertension or reduce blood pressure levels. A secondary aim of this study is to conduct a meta-analysis to summarize intervention effectiveness.

Data sources and strategy

We searched PubMed, Embase and Web of Science from January 2008 to November 2018. This time frame was selected to encompass studies that would have likely benefited from recent development and improvement in natural and quasi- experiments [ 13 , 20 ]. Briefly, the search strategy consisted in intersecting keywords related to the study methods (e.g., natural experiments, quasi-experiments, DID, synthetic control, interrupted time series, etc.) with the environment or settings (e.g., community, nation, organization, etc.) and the outcome (e.g., hypertension, elevated blood pressure, etc.). The full search strategy is described in Table S 1 . This systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement [ 21 ] (Fig. 1 ).

Study search and selection flow

Study selection

Two trained members (TX, FZ) screened abstracts and full-text articles. Disagreements were decided by a third member (RN). We included studies that used natural and quasi-experiments to evaluate interventions aimed at preventing hypertension, controlling hypertension or reducing blood pressure levels. The outcome measures were prevalence of hypertension and changes in mean blood pressure. Studies were excluded if they were not in English, were not a natural experiment or a quasi-experimental design, did not include a control group (as it has higher risk to internal validity due to the absence of comparison to adjust for time trends and confounding) [ 22 ], did not include blood pressure or hypertension as their outcome or included participants that were 13 years old or younger. In addition, we excluded studies that were not original research articles (e.g., study protocol, books, commentary, dissertations, conference proceedings, comments, systematic reviews, modeling and simulation studies), or had no full text available.

Data extraction and quality assessment

The following information was extracted: study design, sample size, study duration, data source, geographic location, participants’ socio-demographic characteristics, intervention types, intervention levels (e.g., individuals, community, school, clinic and national levels as suggested by the socio-ecological model [ 23 ]), behavior targeted and outcome measures (prevalence of hypertension or mean blood pressure change) (Table 1 , Table S 2 ).

The interventions were classified by strategies into four types:

Education and counseling: This subcategory includes strategies that aim at educating and providing knowledge and counseling to participants on lifestyle modifications (e.g., increasing physical activity (PA), eating better, avoiding or stopping smoking, etc.).

Management: This subcategory includes strategies that aim at monitoring patients’ metabolic factors and chronic diseases (e.g., blood pressure, cholesterol level, etc.) as well as patients’ adherence to medication. These strategies are generally done or facilitated by physicians, general practitioners (e.g., by assessing computerized clinical guidelines in the electronic health record management system), nurses, other staffs, or patients themselves.

Education, counseling and management: This subcategory combines education and counseling strategies with management strategies as described above.

Screening and referral for management: This subcategory includes strategies that aim at screening for (i.e., checking for the presence of) economic risk factors, medical needs, and CVD risk factors, followed by the referral of participants who screened positive to professionals who specialize in the management of those needs.

We also classified the interventions by settings into (1) community level; (2) health center level (i.e., primary care center or general practices), (3) organization level and (4) nationwide. In addition, we have classified the intervention by duration of the study into short-term (i.e., participants were followed for less than 12 months) and long-term (i.e., participants were followed for longer than or equal to 12 months).

We implemented the Cochrane Risk of Bias Tool for risk of bias and used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to assess the quality of the evidence for mean blood pressure change outcome [ 50 ], since the meta-analysis focused on this outcome. The risk of bias for studies included in this review could be found in Table S 3 and the quality of studies has also been summarized in Table S 4 .

Meta-analysis

To summarize the effectiveness of interventions on mean blood pressure changes, we also conducted a meta-analysis. Due to the high heterogeneity in the studies and interventions, we undertook a random-effects model and only summarized the effectiveness of intervention strategies by subgroup defined by intervention types, settings and duration. We estimated the weighted mean difference (WMD) of blood pressure and 95% confidence intervals (CIs). The studies included in the meta-analysis were only those whose outcomes were mean differences (MDs) in blood pressure ( n = 27) [ 16 , 19 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ] as these studies provided the data needed for performing the meta-analysis. Three studies [ 38 , 39 , 43 ] were excluded as they did not provide enough information to compute the standard errors (SEs). To estimate the average effect of the intervention when not directly provided, we subtracted the before-and-after change in the intervention group from that in the control group or subtracted the intervention-to-control difference at follow-up to that at baseline (pre-post design with a control group). Methods to calculate intervention impact and SEs were outlined in the appendix (Figs. S 1 , S 2 , Table S 5 ).

We presented the meta-analysis results using forest plots (Table 2 , Fig. 2 , Figs. S 3 , S 4 ). We assessed the heterogeneity by using the I 2 (Table 2 , Fig. 2 , Figs. S 3 , S 4 ). We did not perform meta-regression as it is not recommended when the number of studies is small (< 10 studies per covariate) [ 51 ]. We assessed publication bias by using funnel plots of SEs (Figs. S 5 , S 6 , S 7 ). To test the robustness of our results, we performed sensitivity analyses by removing one study at a time from the pool of studies to assess its impact on the findings (Tables S 6  , S 7 , S 8 , Figs. S 8 , S 9 , S 10 ). Data were analyzed with Stata 15.1 (StataCorp LLC, College Station, TX, USA).

Forest plot stratified by intervention types for blood pressure. A Forest plot stratified by intervention types for systolic blood pressure (SBP). B Forest plot stratified by intervention types for diastolic blood pressure (DBP)

Overall, 788 titles of potentially relevant studies were identified and screened. In total, 545 were excluded and 243 full papers were retrieved, then 30 studies were included in the final sample ( Fig. 1 ) .

Study characteristics

Of the 30 studies included in this review [ 16 , 17 , 18 , 19 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ], three studies reported changes in hypertension prevalence, among which one study reported preventing hypertension in the general population [ 24 ] and two studies reported blood pressure control in patients with hypertension [ 17 , 18 ]; 25 studies reported mean blood pressure changes [ 16 , 19 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]; two studies reported both outcome measures (changes in hypertension prevalence and mean blood pressure changes) [ 25 , 26 ]. Thirteen studies used education and counseling intervention strategies [ 24 , 25 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]; four studies used management intervention strategies [ 18 , 19 , 38 , 39 ]; seven studies combined education, counseling and management intervention strategies [ 26 , 40 , 41 , 42 , 43 , 44 , 45 ]; and six studies used screening and referral for management intervention strategies [ 16 , 17 , 46 , 47 , 48 , 49 ]. Fourteen studies followed participants for less than 12 months (i.e., short-term interventions) [ 17 , 26 , 27 , 29 , 30 , 32 , 33 , 34 , 36 , 40 , 41 , 42 , 43 , 45 ]. Twelve studies were conducted in the US [ 16 , 17 , 19 , 24 , 27 , 28 , 32 , 33 , 39 , 41 , 43 , 46 ] and most studies included both genders [ 16 , 17 , 18 , 19 , 24 , 25 , 26 , 28 , 29 , 30 , 31 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ] and all racial/ethnic groups [ 16 , 17 , 18 , 19 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. We found no natural experiments according to the definition used in this study (Table 1 , Table S 2 ).

Quality ratings

According to the Cochrane Risk of Bias Tool, most studies included in this review were found to have a high risk of bias ( Table S 3 ). This was so because the Cochrane Risk of Bias Tool was mostly designed for RCTs. Studies included in this review only used quasi-experiment designs and as such did not use randomization, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment. Using the GRADE approach, the quality of evidence was deemed of low quality for the mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) change outcome (Table S 4 ).

Studies that reported prevalence of hypertension in the general population or changes in the prevalence of controlled blood pressure in hypertension patients after intervention

Outcome of interest: prevention of hypertension in healthy people, education and counseling intervention strategies.

Two studies evaluated the education and counseling intervention strategies, and both found that those strategies could help prevent hypertension in healthy people [ 24 , 25 ]. One study in the US found that nutritional education and giving access to fruits and vegetables through community gardens helped reduce hypertension prevalence (61.0% vs. 45.0%; P < 0.01), whereas the prevalence of hypertension in the control group did not change (46.7% vs. 49.8%; P = 0.39) [ 24 ]. The other study in Africa showed that an education strategy which promoted PA and healthy diet and combined with free smoking cessation consultations could help reduce the prevalence of hypertension (22.8% vs. 16.2%; P = 0.01), compared to that in control group (14.0% vs. 15.1%; P = 0.52) [ 25 ].

Outcome of interest: improvement of hypertension control in patients with hypertension

Management intervention strategies.

A study in the US showed that patients whose general practitioners accessed the computerized clinical practice guideline at least twice a day improved their hypertension control compared to the patients whose general practitioners never accessed the computerized clinical practice guideline ( P < 0.001) [ 18 ].

Education, counseling and management intervention strategies

A study in the US found that patients who received education about hypertension and did home blood pressure monitoring had a better control of their hypertension compared to the control group ( P = 0.03) [ 26 ].

Screening and referral for management intervention strategies

A study in the US showed that for White patients, interventions which involved a coordinator who identified and reached out to patients not meeting CVD goals and linked them to management programs could improve the odds of blood pressure control (odds ratio, 1.13; 95% CI, 1.05 to 1.22) compared to no intervention [ 17 ].

Studies that reported mean blood pressure changes after intervention

Outcome of interest: reduction in mean blood pressure.

Seven [ 25 , 27 , 28 , 29 , 30 , 34 , 35 ] of twelve [ 25 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ] (58.3%) studies showed that the education and counseling intervention strategies could help reduce mean blood pressure compared to the control group. Education and counseling interventions targeting lifestyle modifications (e.g., diet and PA) have been found effective in reducing blood pressure in the workplace. A study in US female nursing assistants found that combining education and continuing motivation (e.g., counseling on questions of interventions and receiving feedback) on diet and PA led to more reduction in DBP compared to the control group who only received the education (MD, − 6.70 mmHg; 95% CI, − 13.35 to − 0.05) [ 27 ]. Two other studies also found that multi-component lifestyle interventions in the workplace including sharing health information by messages, putting up posters, using pedometers, and giving education on PA could help healthy employees or employees with hypertension lower blood pressure [ 28 , 29 ]. Besides the workplace, interventions implemented in a community setting also appeared to work in reducing blood pressure. A study that included participants age 55 years or more in Asia found that people who attended 60-min Tai Chi three times per week for 12 weeks had a larger reduction in SBP (MD, − 14.30 mmHg; 95% CI, − 19.20 to − 9.40) and in DBP (MD, − 7.02 mmHg; 95% CI, − 10.62 to − 3.42) compared to people maintaining usual daily activities [ 30 ]. Another study among patients with hypertension in Asia found that education about the nutritional behavior and guidelines from dietary approaches to stop hypertension (DASH) approach could help reduce blood pressure more in the intervention group compared to the control group who only received the instruction booklets used in intervention group (SBP: MD, − 13.50 mmHg; 95% CI, − 16.15 to − 10.85; DBP: MD, − 6.60 mmHg; 95% CI, − 8.17 to − 5.03) [ 34 ]. One study in Africa also showed that education on promoting PA and healthy diet, combined with free smoking cessation consultations could help reduce SBP in the intervention group [ 25 ].

Two [ 19 , 39 ] of three [ 19 , 38 , 39 ] (66.7%) studies showed that the management intervention strategies could help reduce mean blood pressure compared to the control group. A study in the US showed that supporting diabetes patients’ self-management of hypertension by team-based chronic models (e.g., proactive patient outreach, depression screening, and health coaching) could decrease more DBP over a 6-month period compared to the usual care (MD, − 1.13 mmHg; 95% CI, − 2.23 to − 0.04) [ 19 ]. A study among hypertension patients in Asia showed that improving the social health insurance system by increasing outpatient expenditure reimbursement ratio could help reduce more SBP (MD, − 2.9 mmHg; P = 0.01) compared to outpatient expense not covered [ 38 ]. The other study among diabetes patients in the US also showed that team-based treatment with trained staff on medical management and self-management helped lower SBP (MD, − 0.88 mmHg; P = 0.01), but it did not compare the MD between treatment and control group [ 39 ].

Six [ 26 , 40 , 42 , 43 , 44 , 45 ] of seven [ 26 , 40 , 41 , 42 , 43 , 44 , 45 ] (85.7%) studies showed that the combination of education, counseling and management intervention strategies led to more blood pressure reduction compared to the control group. One study among hypertension patients in Europe found that management of stress by biofeedback-assisted relaxation and lifestyle counseling on diet and PA reduced more SBP (MD, − 2.62 mmHg; 95% CI, − 3.96 to − 1.29) and DBP (MD, − 1.00 mmHg; 95% CI, − 1.90 to − 0.93) compared to the control group [ 40 ]. One study among hypertension patients in the US also found that education about hypertension and home blood pressure monitoring could help reduce more SBP (MD, − 4.70 mmHg; 95% CI, − 7.14 to − 2.26) and DBP (MD, − 2.20 mmHg; 95% CI, − 3.80 to − 0.60) compared to controls [ 26 ]. A study among 65-year-and-older hypertension patients in Asia found that the intervention group who received education on hypertension management, community-based eHealth monitoring, and monthly telephone counseling had more reduction in SBP (MD, − 10.80 mmHg; 95% CI, − 14.99 to − 6.61) compared to the control group who only received a poster about hypertension management [ 42 ]. A study among hypertension patients in the US also showed that interventions on lifestyle modifications, and nutritional, pharmacological therapies as well as medication adherence lowered SBP and DBP compared to the control group [ 43 ]. A study among hypertension patients in Asia found that integration of preventive-curative services delivery and cooperation among village-town-county physicians for education on lifestyle modifications, taking blood pressure drugs regularly and monitoring the blood pressure could help reduce blood pressure more in the intervention group [ 44 ]. The other study in Asia also found that integrated program with health education on home blood pressure monitoring and hypertension measurement skills could help reduce blood pressure more in the intervention group [ 45 ].

Four [ 16 , 46 , 47 , 48 ] of five [ 16 , 46 , 47 , 48 , 49 ] (80.0%) studies showed that the screening and referral for management intervention strategies could help reduce more blood pressure compared to the control group. Screening for medical or economic needs followed by offering treatment and resources has been found helpful. One study in the US found that screening for unmet needs in primary care and offering those who screened positive some resources could reduce SBP (MD, − 2.6 mmHg; 95% CI, − 3.5 to − 1.7]) and DBP (MD, − 1.4 mmHg; 95% CI, − 1.9 to − 0.9) in patients [ 16 ]. The other study among patients with serious mental illness in the US also found that using registry for general medical needs and outcomes, screening and referral for general medical illness prevention and treatment could help reduce more DBP compared to controls (MD, − 3.00 mmHg; 95% CI, − 4.96 to − 1.04) [ 46 ]. Assessing and screening CVD risk followed by a management program has also been found beneficial to reduce blood pressure. A study in Europe showed that participating in CVD risk assessment and management program, including screening and tailored strategies for lifestyle advice on CVD risk factors could reduce more SBP (MD, − 2.51 mmHg; 95% CI, − 2.77 to − 2.25) and DBP (MD, − 1.46 mmHg; 95% CI, − 1.62 to − 1.29) compared to controls [ 47 ]. A study among hypertension patients in Asia also found that a standardized CVD-risk assessment, a hypertension complication screening and adherence to medications could help reduce more blood pressure compared to the usual care [ 48 ].

Meta-analysis of the effectiveness of interventions on mean blood pressure change

Intervention type sub-group analysis.

The largest blood pressure reduction (SBP: WMD, − 5.34 mmHg; 95% CI, − 7.35 to − 3.33; DBP: WMD, − 3.23 mmHg; 95% CI, − 5.51 to − 0.96) was seen for interventions that combined education, counseling and management intervention strategies (Table 2 , Fig. 2 ).

Intervention setting sub-group analysis

Participants who experienced interventions implemented in community settings (WMD, − 3.77 mmHg; 95% CI, − 6.17 to − 1.37) and in health center settings (WMD, − 3.77 mmHg; 95% CI, − 5.78 to − 1.76) had large SBP reduction. Participants experienced interventions implemented in organization settings had large DBP reduction (WMD, − 3.92 mmHg; 95% CI, − 5.80 to − 2.04) (Table 2 , Fig. S 3 ).

Intervention duration sub-group analysis

Participants who were followed for less than 12 months (i.e., short-term interventions) had a large reduction in blood pressure (SBP: WMD, − 6.25 mmHg; 95% CI, − 9.28 to − 3.21; DBP: WMD, − 3.54 mmHg; 95% CI, − 5.21 to − 1.87) and participants who were followed for longer than or equal to 12 months (i.e., long-term interventions) had a moderate reduction in blood pressure (SBP: WMD, − 1.89 mmHg; 95% CI, − 2.80 to − 0.97; DBP: WMD, − 1.33 mmHg; 95% CI, − 2.11 to − 0.55) (Table 2 , Fig. S 4 ).

We summarized the evidence from quasi-experiments that have evaluated interventions used to (1) prevent hypertension in the general population, (2) improve hypertension control in patients with hypertension or (3) reduce blood pressure levels in both the general population and patients.

In this systematic review, we found that the intervention strategies such as (1) education and counseling, (2) management, (3) education, counseling and management and (4) screening and referral for management were beneficial in preventing, controlling hypertension or reducing blood pressure levels. In particular, we found that education and counseling on lifestyle modifications (i.e., promoting PA, healthy diet, smoking cessation consultations) could help prevent hypertension in healthy people. The use of computerized clinical practice guidelines by general practitioners, education and management of hypertension, screening for CVD goals and referral to management could help improve hypertension control in patients with hypertension. The education and counseling on lifestyle modifications, the monitoring of patients’ metabolic factors and chronic diseases (e.g., blood pressure, cholesterol level, etc.) as well as patients’ adherence to medication, the combined education and management of hypertension, the screening for economic risk factors, medical needs, and CVD risk factors, followed by the referral to management all could help reduce blood pressure levels. Our study is one of the few systematic reviews that have summarized the evidence from quasi-experiments on hypertension prevention and control. A previous systematic review [ 52 ] which summarized evidence from cluster-randomized trials and quasi-experimental studies had been conducted and found that education, counseling and management strategies were also beneficial in controlling hypertension and reducing blood pressure. It showed that educating healthcare providers and patients, facilitating relay of clinical data to providers, promoting patients’ accesses to resources were associated with improved hypertension control and decreased blood pressure [ 52 ]. Another systematic review which summarized evidence from RCTs found that several interventions including blood pressure self-monitoring, educational strategies, improving the delivery of care, and appointment reminder systems could help control hypertension and reduce blood pressure [ 6 ]. Another study also found that community-based health workers interventions including health education and counseling, navigating the health care system, managing care, as well as giving social services and support had a significant effect on improving hypertension control and decreasing blood pressure [ 53 ]. A review from observational studies and RCT evidence from the US Preventive Services Task Force found that office measurement of blood pressure could effectively screen adults for hypertension [ 7 ].

Our review did not find natural experiments studies according to the definition used in this study. Quasi-experimental designs included DID, propensity score matching and pre-post designs with a control group (PPCG). While PPCG designs generally involve two groups (intervention and control) and two different time points (before and after the intervention), DID designs generally involve two or more intervention and control groups and multiple time points [ 13 ]. In this review, we did not include pre-post without a control group design because of its higher risk to internal validity due to the absence of comparison to adjust for time trends and confounding [ 22 ]. The findings in this review, highlight that, quasi-experiments are increasingly used to evaluate the effectiveness of health interventions for hypertension management when RCTs are not feasible or appropriate. For instance, several studies included in our systematic review often indicated that RCTs would have been difficult to be implemented given that the intervention was conducted in a particular setting such as a pragmatic clinical setting [ 16 , 43 , 45 , 48 ], a community setting [ 24 , 35 , 36 , 42 ], or a real-world organizational setting [ 33 ] because of ethical concerns and human resources issues. Another reason why quasi-experiments were chosen had to do with the need for translation and generalizability of the evidence in a specific community setting [ 32 ]. In fact, RCTs are not always generalizable to the communities or settings of interests [ 11 ]. The growing interest in and hence the increase in the use of natural and quasi-experiments in public health may be due to the recognition and realization of its usefulness in evaluating health interventions [ 14 , 54 ].

Given that there was high heterogeneity in the studies included in this systematic review, we have performed a random effects model and have only presented the subgroup analysis by intervention types, settings and duration of the study. Overall, our study suggested that interventions that combined education, counseling and management strategies appeared to show a relatively large beneficial effect for reducing blood pressure. However, our finding should be interpreted with caution due to the high-risk of bias and lower quality of evidence given the quasi-experimental nature of the designs (as opposed to evidence from randomized experiments). Nevertheless, the findings here can give us some insights on the benefit of interventions such as education, counseling and management, especially given that our findings are in line with previous studies [ 6 , 8 , 52 , 55 ]. Given that RCTs are not always feasible or appropriate, scientists should develop more rigorous methods to increase the internal validity of non-randomized studies. Compared to previous studies, one systematic review with meta-analysis including cluster-randomized trials and quasi-experiment studies showed that multi-component interventions which incorporated education of health care providers and patients, facilitating relay of clinical data to providers, and promoting patients’ accesses to resources could reduce more blood pressure compared to controls [ 52 ]. A recent systematic review with meta-analysis of RCTs also reported that interventions which included blood pressure self-monitoring, appointment reminder systems, educational strategies, and improving the delivery of care showed beneficial effects on lowering blood pressure [ 6 ]. Another systematic review and meta-analysis of RCTs also showed that self-measured blood pressure monitoring lowered SBP by 3.9 mmHg and DBP by 2.4 mmHg at 6 months compared to the usual care group [ 8 ]. One systematic review and meta-analysis of RCTs found that diet improvement, aerobic exercise, alcohol and sodium restriction, and fish oil supplements reduced blood pressure as well [ 55 ].

Limitations

This review has some limitations. First, the definition of natural and quasi-experiments is not consistent across fields. Second, the main limitation in most if not all the quasi-experimental study designs noted in this review was the potential for unobserved and uncontrolled confounding, which is a threat to internal validity and could lead to biased findings. Third, our findings may not be generalizable to all countries and settings as we only included studies published in the English language in this review. Fourth, as is the case in most other reviews, we could have missed relevant studies despite our best attempt to conduct a thorough search of the literature. Fifth, we found that most studies included in this study had a high risk of bias. It might be because we used the Cochrane Risk of Bias Tool to assess bias which was designed for examining RCTs. Studies in this review only used quasi-experiment designs and did not have randomization, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment. Sixth, studies generally reported the measure of intervention impact differently across studies, making it difficult to combine the findings. In addition, studies were highly heterogeneous in terms of the types of individuals included in the study (e.g., healthy individuals and patients). We conducted the subgroup meta-analysis to reduce the heterogeneity, but the high heterogeneity still existed. Therefore, the results from meta-analysis need to be interpreted with caution. The individual impact reported for each individual study and the results from systematic review should be given more consideration.

In this systematic review, interventions that used education and counseling strategies; those that used management strategies; those that combined education, counseling and management strategies and those that used screening and referral for management strategies were beneficial in preventing, controlling hypertension and reducing blood pressure levels. The combination of education, counseling and management strategies appeared to be the most beneficial intervention to reduce blood pressure levels. The findings in this review, highlight that, a number of interventions that aim at preventing, controlling hypertension or reducing blood pressure levels are being evaluated through the use of quasi-experimental studies. Given that RCTs are not always feasible or appropriate, scientists should develop more rigorous methods to increase the internal validity of such quasi-experimental studies.

Availability of data and materials

The data supporting the conclusions of this article is included within the article and the additional file.

Abbreviations

Confidence interval

Cardiovascular disease

Dietary approaches to stop hypertension

Diastolic blood pressure

Difference-in-difference

Grading of Recommendations, Assessment, Development, and Evaluation

Mean difference

Physical activity

Pre-post designs with a control group

Randomized clinical trial

Systolic blood pressure

Standard error

United States

Weighted mean difference

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TX participated in the study conception, design and analysis and wrote the initial first draft of the article. FZ participated in the study conception, design and reviewed the first draft of the article. RN conceived and supervised the design and analysis, finalized the first draft and critically reviewed and revised the manuscript. All authors provided critical input and insights into the development and writing of the article and approved the final manuscript as submitted.

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Additional file 1: table s1..

Search words. Table S2. Summary of the characteristics of the studies included in this review ( n = 30). Table S3. Risk of Bias Tool Assessments Across Studies (n = 30). Table S4. GRADE Evidence Profiles Across Studies in Meta-analysis ( n = 24). Table S5. Estimates and parameters in studies that reported on the mean difference in blood pressure ( n = 27). Table S6. Sensitivity analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP) in meta-analysis stratified by intervention type. Table S7. Sensitivity analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP) in meta-analysis stratified by intervention setting. Table S8. Sensitivity analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP) in meta-analysis stratified by intervention duration. Fig. S1. Methods to calculate mean differences (MD). Fig. S2. Methods to calculate standard errors (SE). Fig. S3. Forest plot stratified by intervention settings for blood pressure. (A) Forest plot stratified by intervention settings for systolic blood pressure (SBP). (B) Forest plot stratified by intervention settings for diastolic blood pressure (DBP). Fig. S4. Forest plot stratified by intervention duration for blood pressure. ( A) Forest plot stratified by intervention duration for systolic blood pressure (SBP). ( B) Forest plot stratified by intervention duration for diastolic blood pressure (DBP). Fig. S5. Funnel plot of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention types. Fig. S6. Funnel plot of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention settings. Fig. S7. Funnel plot of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention duration. Fig. S8. Sensitivity analysis of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention types. Fig. S9. Sensitivity analysis of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention settings. Fig. S10. Sensitivity analysis of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention duration

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Xia, T., Zhao, F. & Nianogo, R.A. Interventions in hypertension: systematic review and meta-analysis of natural and quasi-experiments. Clin Hypertens 28 , 13 (2022). https://doi.org/10.1186/s40885-022-00198-2

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• Hypertension
• Non-randomized controlled trials as topic
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Clinical Hypertension

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Guideline-Driven Management of Hypertension: An Evidence-Based Update

Affiliations.

• 1 Department of Medicine, University of Virginia Health System, Charlottesville (R.M.C).
• 2 Department of Medicine, Case-Western Reserve University School of Medicine, Cleveland, OH (J.T.W.).
• 3 Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN (S.J.T.).
• 4 Departments of Epidemiology and Medicine, Tulane University, New Orleans, LA (P.K.W.).
• PMID: 33793326
• PMCID: PMC8034801
• DOI: 10.1161/CIRCRESAHA.121.318083

Several important findings bearing on the prevention, detection, and management of hypertension have been reported since publication of the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline. This review summarizes and places in context the results of relevant observational studies, randomized clinical trials, and meta-analyses published between January 2018 and March 2021. Topics covered include blood pressure measurement, patient evaluation for secondary hypertension, cardiovascular disease risk assessment and blood pressure threshold for drug therapy, lifestyle and pharmacological management, treatment target blood pressure goal, management of hypertension in older adults, diabetes, chronic kidney disease, resistant hypertension, and optimization of care using patient, provider, and health system approaches. Presenting new information in each of these areas has the potential to increase hypertension awareness, treatment, and control which remain essential for the prevention of cardiovascular disease and mortality in the future.

Keywords: American Heart Association; antihypertensive agents; blood pressure; cardiovascular disease; hypertension; mortality.

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• Drug Resistance
• Heart Disease Risk Factors
• Hyperaldosteronism / complications
• Hypertension* / diagnosis
• Hypertension* / etiology
• Hypertension* / prevention & control
• Hypertension* / therapy
• Hypertension, Renovascular / therapy
• Meta-Analysis as Topic
• Observational Studies as Topic
• Randomized Controlled Trials as Topic
• Renal Insufficiency, Chronic / therapy
• Young Adult
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Top Ten Breakthroughs in Clinical Hypertension Research in 2022

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Hypertension is a major global public health concern whose disease burden affects an estimated 1.4 billion people worldwide and is associated with 10.8 million deaths annually. Despite substantial advances in medical care, the prevalence of hypertension has markedly increased, owing to population aging; poor treatment adherence; and increases in risk factors, such as excessive salt intake, and overweight and obesity. Consequently, the disability-adjusted life years have increased by 40%, primarily because of elevated risk of stroke, coronary atherosclerosis, heart failure, and kidney failure. Major outstanding problems associated with the treatment and management of hypertension include determining optimal blood pressure targets, developing innovative antihypertensive medications and devices, and implementing effective and feasible hypertension management strategies. To address these challenges, numerous clinical trials are currently underway. This article highlights the most influential ten clinical studies on hypertension in 2022. The rational use of antihypertensive medications is concluded to be important for effective hypertension management. Important considerations include medication types and dosing times; optimal blood pressure targets; the development of new drugs and therapeutic devices; specific community characteristics, such as village doctor-led care; and healthful diets.

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Nonstandard Abbreviations and Acronyms: ACC, American College of Cardiology; AHA, American Heart Association; BP, Blood pressure; CVDs, Cardiovascular diseases; DBP, Diastolic blood pressure; EBA, Endovascular baroreflex amplification; ESC, European Society of Cardiology; RDN, Renal denervation; SBP, Systolic blood pressure

The Best Time to Take Antihypertensive Medication—TIME Study

The circadian rhythm of blood pressure (BP) shows a dipper pattern, defined by low BP during sleep and peaks after awakening. A non-dipper rhythm, including nocturnal and morning hypertension, is considered an important predictor of adverse cardiovascular outcomes [ 1 , 2 ], and its management has been emphasized in The HOPE Asia network 2022 update consensus statement [ 3 ]. Moreover, taking antihypertensive medication in the evening has been demonstrated to normalize the circadian BP rhythm [ 4 ], thus leading to the hypothesis that evening administration of antihypertensive medication may improve cardiovascular outcomes more effectively than morning administration. This hypothesis has been strongly supported by the MAPEC trial (RR=0.33, 95% CI 0.19–0.55) and the Hygia trial (RR=0.58, 95% CI 0.49–0.68) [ 5 , 6 ]. However, the design of these trials was flawed, primarily because of issues with the randomization process. Furthermore, although significant differences were observed between the treatment and control groups after 1 year, the overall trial duration was 6.3 years, thus leading to ethical concerns. Consequently, the interpretation of the findings from these two studies remains debated in the scientific community [ 7 , 8 ].

The results of the Treatment in Morning versus Evening (TIME) study, a prospective, pragmatic randomized controlled clinical study by Thomas M MacDonald, were presented at the European Society of Cardiology (ESC) Congress 2022. A total of 21,104 adults with hypertension who were taking at least one antihypertensive medication were recruited. The participants were randomly assigned to a morning (06:00–10:00) or an evening (20:00–00:00) medication administration group by a computer algorithm generated through a randomization process, with no restriction, stratification, or minimization randomization methods. Because of the nature of the intervention, neither patients nor investigators were blinded to the group allocation. However, the endpoint assessors were blinded to group allocation to minimize potential bias in the study results.

The primary outcome was a composite of vascular death or hospitalization for non-fatal myocardial infarction or non-fatal stroke. The results indicated no statistically significant differences in cardiovascular outcomes between groups (HR=0.95, 95% CI 0.83–1.10, P=0.53).

The secondary outcomes included the components of the primary outcome, all-cause mortality, and hospitalization or death from congestive heart failure. No statistically significant differences were found in any outcomes.

Moreover, taking medication in the evening was found to be safe, because a lower incidence of falls and comparable incidence of fractures were observed the evening dosing group.

Outcomes were assessed with an unadjusted Cox proportional hazards model, Yates’ chi-square test, or t-test, as appropriate. The median follow-up time was 5.2 (IQR 4.9–5.7) years.

The results were published in The Lancet [ 9 ], which concurrently commented that the TIME study demonstrated that the optimal dosing time of antihypertensive medication should be decided jointly by patients and clinicians, according to each patient’s lifestyle and situation, to achieve the best medication adherence and optimal BP control [ 10 ].

The findings of the TIME study markedly differed from those of the aforementioned MAPEC and Hygia trials; this discrepancy has prompted reevaluation of the optimal antihypertensive medication dosing time. In addition, two similar clinical trials, the BedMed (NCT02990663) and BedMed-Frail (NCT04054648) trials, are currently being conducted to investigate the effects of antihypertensive medication timing on morbidity and mortality in patients with hypertension. The BedMed-Frail trial specifically focuses on the frail population [ 11 ]. The findings of these studies are expected to provide valuable guidance for the development of future hypertension guidelines, which currently lack specific recommendations regarding the optimal timing of antihypertensive medication. However, the TIME study did not investigate the effects of different antihypertensive medications on cardiovascular outcomes associated with morning or evening dosing; such an investigation would enable more precise and detailed intervention guidance regarding the dosing time of hypertension medication. Thus, further investigations in this area are necessary.

Effects of Renal Denervation on Blood Pressure—Spyral HTN-ON MED Pilot Study With Long-Term Follow-up for 3 years

To achieve the target BP, multiple antihypertensive medications are frequently prescribed in numerous patients, thus often resulting in low adherence, drug intolerance, and high healthcare costs. Consequently, novel therapies are needed. With the rapid development of interventional techniques in recent years, transcatheter renal denervation (RDN) has emerged as a potential approach for BP lowering. The unblinded clinical trials SYMPLICITY HTN-1 and HTN-2 have indicated significant decreases in systolic BP (SBP) 6 months after RDN, by 25 mmHg and 33 mmHg, respectively [ 12 , 13 ]. However, the blinded and sham-controlled SYMPLICITY HTN-3 trial has demonstrated no significant differences in SBP and 24-hour ambulatory SBP at 6 months between patients who underwent RDN and sham surgery. The discrepant results observed between the SYMPLICITY HTN trials may be attributable to various factors, including differences in the trial design, patient populations, and execution of the RDN procedure. The rigorous design of the HTN-3 trial effectively eliminated regression to the mean, and the Hawthorne and placebo effects. However, the uncertain adherence to medication between groups and the suboptimal execution of the RDN procedure as a result of operators’ limited experience in the HTN-3 trial might have introduced confounding effects, thereby hindering the ability to distinguish between the experimental and control groups, and leading to an absence of statistically significant results [ 14 ]. Therefore, caution is warranted in interpreting the 6-month follow-up results of the HTN-3 trial. Consequently, studies were subsequently conducted to further elucidate the role of RDN in the management of hypertension [ 15 – 19 ].

The 3-year follow-up results of SPYRAL HTN-ON MED, a randomized, single-blind, sham-controlled clinical study, were presented at the American College of Cardiology (ACC) Conference 2022. The study enrolled 80 patients meeting the inclusion criteria of SBP of 150–180 mmHg, diastolic BP (DBP) of at least 90 mmHg, mean 24-hour SBP of 140–170 mmHg, and taking one to three antihypertensive medications. The patients were randomly assigned to either a radiofrequency RND group (n=38) or a sham group (n=42).

The primary outcome was the difference in 24-hour SBP at 6 months between the RDN group and the sham group. The RDN group, compared with the sham group, demonstrated a reduction of 7 mmHg (95% CI −12.0 to −2.1) in 24-hour SBP and 4.3 mmHg (95% CI −7.8 to −0.8) in 24-hour DBP [ 15 ]. After 3 years of follow-up, the RDN group exhibited reductions of 10.0 mmHg (95% CI −16.6 to −3.3) and 4.3 mmHg (95% CI −10.1 to −1.8) in 24-hour SBP and DBP, respectively compared to the sham group.

The secondary outcome included assessment of changes in 24-hour, morning, daytime, nighttime, and office SBP changes at 24 and 36 months; statistically significant differences were observed in all these measures.

Outcomes were assessed in SAS statistical software with T-tests or analysis of covariance, as appropriate.

The Lancet published results demonstrating that radiofrequency RDN consistently and significantly decreases BP in patients with hypertension without serious adverse events, independently of the antihypertensive medications taken. Moreover, after 3 years of RDN treatment, the observed 10 mmHg decrease in 24-hour SBP was sustained throughout the day and was associated with significantly lower rates of cardiovascular outcomes, thus suggesting that RDN may potentially be a viable alternative for patients with resistant hypertension, or those unwilling or unable to tolerate multiple antihypertensive medications [ 20 , 21 ].

The results of several other RDN clinical trials were reported in 2022. The 6-month follow-up results of the Spyral HTN-ON MED Expansion study, which were presented at American Heart Association (AHA) Scientific Sessions 2022, indicated that the RDN group, compared with the sham group, had a significant reduction of 3.7 mmHg (P=0.001) in nocturnal ambulatory SBP. However, the 24-hour SBP change between groups was 1.9 mmHg (P=0.119), which didn’t meet the primary endpoint. In addition, the 3-year follow-up results of the SYMPLICITY HTN-3 study were reported in The Lancet [ 22 ]. The difference between the RDN and sham groups was 22.1 mmHg (95% Cl −27.2 to −17.0) in SBP and 16.5 mmHg (95% CI −20.5 to −12.5) in 24-hour SBP, The distinct difference, in contrast with the negative results of 6-month follow-up, confirms the effectiveness and long-term durability of RDN. Furthermore, the 3-year follow-up results of the Global SYMPLICITY Registry study were reported in JACC [ 23 ]. After RDN, a sustained average 16.7 mmHg decrease in BP over 3 years and a higher amount of time spent in the therapeutic range of BP were observed compared with the baseline, with lower major cardiovascular outcomes. Because of its demonstrated efficacy and safety, RDN is considered a viable antihypertensive therapy in the 2023 Hypertension Guidelines of China, Europe, and the Netherlands [ 24 , 25 ].

However, several limitations should be considered before RDN becomes a standard treatment option for patients with hypertension. First, no clinically convenient and feasible method to detect renal sympathetic nerve activity is currently available. Therefore, the response to RDN in some patients is unsatisfactory. Second, the population of patients optimally suited for RDN has yet to be determined, because the mechanism and effects of RDN have not been fully elucidated. Third, the lack of standardized operation procedures, coupled with challenges in training operators and managing potential interventional complications, pose obstacles to the development of RDN.

Phase II Trial of the Aldosterone Synthase Inhibitor Baxdrostat on Resistant Hypertension—BrigHTN Study

Approximately 10% of individuals with hypertension are classified as having treatment resistance [ 26 ], such that their condition cannot be effectively controlled, even with the administration of multiple antihypertensive medications [ 27 ]. Aldosterone exacerbates hypertension by promoting sodium reabsorption in distal nephrons by increasing the number and opening frequency of epithelium sodium channels, thereby leading to volume expansion. Additionally, aldosterone damages various target organs, including vessels, kidneys, and the heart, via multiple mechanisms, such as upregulation of connective tissue growth factor and subsequent fibrosis; production of proinflammatory molecules contributing to organ and extracellular matrix remodeling; oxidative stress; and stimulation of cell migration, proliferation, and apoptosis [ 28 ]. Moreover, target organ damage may worsen hypertension. Previous studies have explored the effectiveness of mineralocorticoid receptor antagonists in the treatment of hypertension. However, limitations of these treatments have been identified to include adverse events, such as an augmented aldosterone response, hyperkalemia, and gynecomastia. In addition, mineralocorticoid receptor antagonists are not appropriate for patients with intermediate or advanced chronic kidney disease [ 29 ]. Therefore, researchers have focused on another mechanism: the inhibition of aldosterone synthase. Nevertheless, because of the 93% sequence similarity between the enzymes synthesizing aldosterone and cortisol, the development of highly selective inhibitors of aldosterone synthase has led to a bottleneck. However, in recent preclinical and phase I trials, baxdrostat, an oral small-molecule aldosterone synthase inhibitor, has been found to substantially decrease plasma aldosterone levels without a concomitant decline in cortisol levels; these findings have increased interest in, and focus on, the inhibition of aldosterone synthase [ 30 ].

The phase II results of the BrigHTN study, a multicenter, double-blind, dose-ranging randomized controlled trial, were presented at AHA Scientific Sessions 2022. A total of 275 patients with resistant hypertension, defined by a BP above 130/80 mmHg, who were taking at least three antihypertensive medications including a diuretic, were recruited. Patients were randomly assigned to receive baxdrostat at doses of 0.5 mg, 1 mg, or 2 mg once per day, or a placebo for 12 weeks.

The study’s primary efficacy endpoint was the change in mean seated SBP from baseline to the end of the 12-week treatment period. The results indicated that baxdrostat exhibited dose-dependent antihypertensive effect: the mean seated SBP decreased by 20.3 mmHg, 17.5 mmHg, 12.1 mmHg, and 9.4 mmHg in the baxdrostat group with doses of 2 mg, 1 mg, or 0.5 mg, and placebo, respectively. Moreover, the 2 mg baxdrostat group exhibited a significant antihypertensive effect, with placebo-adjusted SBP and DBP decreases of 11.0 mmHg (95% CI −16.4 to −5.5) and 5.2 mmHg (95% CI −8.7 to −1.6).

The secondary outcomes included the change in the mean seated DBP with respect to baseline. The results indicated a difference in DBP between the baxdrostat 2-mg group and the placebo group of 5.2 mmHg (95% CI −8.7 to −1.6).

Safety endpoints included adverse events, vital signs, and the results of physical examinations. Two patients developed high serum potassium levels exceeding 6.0 mmol/L, which did not recur after withdrawal and re-initiation of the drug.

In conclusion, this study first demonstrated significant antihypertensive effectiveness of baxdrostat in patients with resistant hypertension, without any adverse effects on cortisol levels or adrenocortical function, or causing severe hyperkalemia. The results were published in NEJM [ 31 ]. These results highlight the potential for baxdrostat to serve as a new treatment option for diseases including resistant hypertension and primary aldosteronism.

However, because baxdrostat was not compared with existing antihypertensive medications, and the renal function of all participants was normal, further studies are necessary to evaluate the long-term effectiveness and safety of this drug, and to identify patient populations in which its use would be appropriate.

Phase III Trial of Dual Endothelin Antagonist Aprocitentan on Resistant Hypertension—PRECISION study

Prior studies have shown the antihypertensive effects of endothelin receptor antagonists [ 32 , 33 ]. These agents act by blocking the endothelin pathway, which is active primarily in endothelial cells and vascular smooth muscle cells, and is involved in cell proliferation and vessel vasoconstriction. Endothelin levels are known to be elevated in hypertension; diseases susceptible to resistant hypertension, such as obesity and obstructive sleep apnea; and complications associated with resistant hypertension, such as diabetes and chronic renal disease; moreover, the resulting changes in vascular tone contribute to the pathogenesis of hypertension and related cardiovascular diseases (CVDs) [ 34 – 37 ]. Aprocitentan is an oral antagonist of the dual endothelin A and B receptor. In a phase II clinical trial, aprocitentan monotherapy has been found to have more effective antihypertensive effects at doses of 10–25 mg compared to dose of 50 mg [ 38 ].

The phase III results of the PRECISION study, a multicenter, blinded randomized controlled trial, were presented at AHA Scientific Sessions 2022. A total of 730 patients with resistant hypertension were recruited, all of whom had a seated SBP above 140 mmHg and were taking at least three antihypertensive medications including a diuretic. The study comprised three parts. In part 1, participants were randomly assigned in a 1:1:1 ratio to receive aprocitentan at doses of 12.5 mg or 25 mg, or a placebo treatment in a double-blind period for 4 weeks. Then all participants took aprocitentan 25 mg for 32 weeks in part 2. Finally, in part 3, patients were randomly reassigned to two groups (1:1) to receive aprocitentan 25 mg or a placebo treatment in a double-blind period for 12 weeks.

The primary and key secondary endpoints were SBP changes from baseline to week 4 and from medication withdrawal from baseline (at the beginning of part 3) to week 40. From baseline to week 4, SBP decreased by 3.8 mmHg (97.5% CI −6.8 to −0.8) in the 12.5 mg aprocitentan group and 3.7 mmHg (97.5% CI −6.7 to −0.8) in the 25 mg group, as compared with the placebo group. After 4 weeks of medication withdrawal, SBP increased by 5.8 mmHg (95% CI 3.7 to 7.9) in the placebo treatment group compared with the aprocitentan treatment group.

The study indicated that, despite its concurrent use with other antihypertensive medications, aprocitentan produced statistically and clinically significant decreases in BP among patients with resistant hypertension, and this effect was maintained for at least 1 year. The results were published in The Lancet , which commended the remarkably well-designed medication research protocol in this study. Notably, the study revealed that aprocitentan, because of its new pharmacological mechanism, may have the potential to serve as a novel option for more than 100 million patients with resistant hypertension worldwide. Moreover, the study also highlighted the long-term efficacy of aprocitentan. This durable treatment option may effectively prevent cardiovascular events, thus providing the first breakthrough in antihypertensive medication in 30 years.

Nonetheless, the effect of aprocitentan is modest, and its clinical value must be further evaluated by comparison with other fourth-line antihypertensive medications (such as spironolactone) [ 39 , 40 ].

Best Time for Mild Chronic Hypertension Treatment During Pregnancy—CHAP study

Mild chronic hypertension during pregnancy has a prevalence ranging from 0.9% to 1.5%, and is associated with elevated risk of placental abruption, premature birth, low birth weight, and perinatal death, as well as multiple maternal adverse events, such as heart failure, stroke, and acute kidney injury [ 41 – 43 ]. The treatment threshold for pregnant women with chronic hypertension varies among guidelines. Specifically, the American College of Obstetricians and Gynecologists (ACOG) guidelines recommend treatment when the BP is at or above 160/110 mmHg, whereas the cutoff in the ESC guidelines is 150/95 mmHg. The World Health Organization, in contrast, does not have a specific recommendation [ 41 , 44 , 45 ]. Doubts have been raised regarding potential harm to the fetus from reduced uteroplacental circulation and in utero exposure to antihypertensive medications during BP lowering, whereas the benefits to maternal health are unclear, thus futher investigations into therapies for BP between 140–159/90–109 mmHg are required. A previous study with small sample sizes has demonstrated the lack of utility of antihypertensive treatment for mild chronic hypertension during pregnancy [ 46 ], whereas a secondary analysis has indicated a higher risk of adverse outcomes among patients with mild chronic hypertension during pregnancy than those with normal BP, in a BP-dependent manner [ 47 ]. The 2015 randomized controlled study CHIPS has revealed that, in comparison with loosely controlled BP (DBP ≤100 mmHg), strictly controlled BP (DBP ≤85 mmHg) decreases the risk of severe maternal hypertension with no adverse effects on fetal growth; however, no statistically significant difference was observed in pregnancy outcomes within 28 days after delivery [ 48 ]. On the basis of the results, numerous associations have lowered the treatment threshold in their recommendations, except for ACOG and the Society for Maternal Fetal Medicine (SMFM), owing to doubts regarding the low statistical power of the CHIPS study, given that its sample size was smaller than anticipated, and it lacked long-term follow-up.

The results of an open-label, randomized trial with a larger sample size and improved regional and racial representation with respect to prior studies, the CHAP study, were presented at the ACC Conference 2022. A total of 2480 pregnant women with mild chronic hypertension and a single fetus of gestational age less than 23 weeks were included and randomly allocated to either an active treatment group (BP ≤140/90) or a standard treatment group (BP ≤160/105).

The primary outcome was a composite of severe preeclampsia, medically indicated preterm births before 35 weeks, placental abruption, and fetal/neonatal death. Compared with the standard treatment group, the active treatment group maintained lower BP (129.5/79.1 mmHg vs. 132.6/81.5 mmHg) and had a lower incidence of the primary outcome (HR=0.82, 95% CI 0.74–0.92), particularly regarding decreased incidence of preeclampsia and medically indicated preterm births.

In conclusion, the CHAP study has indicated that active antihypertensive treatment (target BP ≤140/90) for mild chronic hypertension during pregnancy considerably decreases adverse pregnancy outcomes without increasing the risk of small-for-gestational-age infants. The results were published in NEJM [ 49 ].

The CHAP study has demonstrated that early-stage antihypertensive therapies are needed for mild chronic hypertension during pregnancy, thus leading to a decrease in the treatment threshold to 140/90 mmHg for pregnant women with chronic hypertension in the updated guidelines issued by SMFM and the Society of Obstetricians and Gynaecologists of Canada in 2022. The updated guidelines may result in more women receiving antihypertensive therapy during pregnancy, thus potentially improving outcomes for both mothers and infants. Healthcare providers should be aware of these updated guidelines, and should consider them when managing hypertension during pregnancy. However, although no statistical differences in neonatal outcomes were observed between groups, the potential long-term effects of active antihypertensive therapies on offspring exposed in utero remain unclear. Therefore, further follow-up studies are necessary to assess the effects on the health and well-being of the offspring. Such research will be crucial to ensure that interventions aimed at improving maternal and fetal health do not have unintended adverse effects on offspring in the long term, and to inform clinical decision-making in this area.

Comparison Between Chlorthalidone and Hydrochlorothiazide for Hypertension—DCP study

Thiazide diuretics, represented by chlorthalidone and hydrochlorothiazide, are the first-line medication recommended by current hypertension guidelines [ 50 ]. Previous studies have illustrated the superiority of chlorthalidone to hydrochlorothiazide [ 51 , 52 ], as also supported by the 2017 ACC/AHA Guidelines for High Blood Pressure [ 53 ], whereas several observational studies have recently demonstrated no significant difference between chlorthalidone and hydrochlorothiazide [ 54 , 55 ]. However, hydrochlorothiazide is more commonly used by clinicians, owing to concerns regarding the hypokalemic effects of chlorthalidone. Thus, further evidence is urgently needed to elucidate current ambiguities.

At AHA Scientific Sessions 2022, the results of the Diuretic Comparison Project (DCP) study, a pragmatic, open-label trial, were presented. A total of 13,523 patients with hypertension, mainly veterans over the age of 65 years, were randomly allocated to a hydrochlorothiazide group (25 or 50 mg/d) or chlorthalidone group (12.5 or 25 mg/d).

The primary outcome was a composite of non-cancer deaths or nonfatal cardiovascular events, defined as nonfatal stroke, myocardial infarction, emergency revascularization for unstable angina, or acute heart failure. The results indicated that during a mean follow-up period of 2.4 years, the incidence of the primary outcome, as well as its components, was comparable (HR=1.04, 95% CI 0.94–1.16) between the chlorthalidone group (10.4%) and the hydrochlorothiazide group (10.0%). Additionally, a subgroup analysis demonstrated that, among participants with a history of myocardial infarction or stroke, the primary outcome was reduced in the chlorthalidone group (HR=0.73, 95% CI 0.57–0.94), whereas among those without such a history, chlorthalidone tended to increase the primary outcome (HR=1.12, 95% CI 1.00–1.26).

Regarding safety outcomes, the incidence of hypokalemia in the chlorthalidone group (6.0%) was higher than that in the hydrochlorothiazide group (4.4%). These findings confirmed clinicians’ longstanding concerns. Moreover, new allergic or adverse reactions were more common in the chlorthalidone group (1.6%) than the hydrochlorothiazide group (0.3%), whereas no statistical difference was found in hospitalization for any cause. Thus, healthcare providers should consider the safety profiles of different diuretics when choosing treatment plans for their patients, and should take steps to minimize the risks of adverse reactions.

The results were published in NEJM [ 56 ]. The DCP study demonstrated that, compared with the clinically commonly used hydrochlorothiazide, chlorthalidone did not decrease the incidence of major cardiovascular outcomes or non-cancer deaths. This discovery challenges the established belief that chlorthalidone is the preferred treatment option, as supported by various guidelines. Therefore, in selecting the antihypertensive medication, consideration of each patient’s medical history, renal function, complications, and other relevant factors is critical in making the most appropriate decision. However, a notable limitation is that this study focused on only participants 65 years of age or older, and the population was predominantly male. Age and sex are important factors influencing the response to antihypertensive therapy and the risk of adverse outcomes. Therefore, the findings of this study may not be directly applicable to younger adults and women, and caution should be exercised when extrapolating the results to these groups. Further studies in different patient populations are necessary to confirm the applicability of these findings.

Effectiveness of Blood Pressure Interventions Led by Village Doctors in Rural China—the CRHCP Study

Approximately 75% of patients with hypertension live in low- and middle-income countries with scarce resources, thus resulting in a low rate of hypertension control [ 57 ]. In rural China, only 5.5% of patients with hypertension have their BP under control [ 58 ]. Village doctors provide basic medical care in rural China and are likely to play a crucial part in the prevention and control of hypertension, if they are properly trained in areas including standardized BP measurement; health coaching on lifestyle modifications; and protocol-driven antihypertensive treatment involving a treatment algorithm, medication selection, contraindications of medications, and adjustment strategies [ 59 , 60 ].

The China Rural Hypertension Control Project (CRHCP) study was a cluster randomized trial initiated by Yingxian Sun at the First Hospital of China Medical University. A total of 33,995 individuals over 40 years of age living in 326 Chinese villages, who had an untreated BP above 140/90 mmHg or treated BP above 130/80 mmHg, were enrolled and randomized (1:1) to an intervention group or a control group receiving conventional antihypertensive medications. In the intervention group, patients received a comprehensive treatment approach initiated by village doctors, including the initiation of antihypertensive medication according to established guidelines, provision of discounted or free medications, guidance on home BP monitoring, health coaching on lifestyle modifications, and organization of social support groups. Follow-up assessments were conducted every 6 months to monitor BP levels and other associated conditions in participants. Notably, however, the study design had several limitations, including practical limitations regarding the recruitment of all patients in a village and variations in the sizes of the clusters. In addition, because the intervention in this study was conducted primarily through oral coaching and guidance by village doctors, the quality of communication between the doctors and patients, as well as patients’ ability to understand and accept treatment, are crucial factors that might have influenced the effectiveness of the intervention. The uncontrollable communication among village doctors and patients between the intervention and control groups might have diminished the observed intervention effect. The phase I (18 months of follow-up) results were presented at AHA Scientific Sessions 2021 and published in The Lancet . The outcome of phase II (36 months of follow-up) was presented at AHA Scientific Sessions 2022 [ 61 ].

The primary outcome was a composite of myocardial infarction, stroke, heart failure requiring hospitalization, and CVD death. The primary outcome rate was substantially lower (HR=0.64, 95% CI 0.58–0.70) in the intervention group (1.6%) than the control group (2.4%).

The secondary outcomes included the components of the primary outcome and death due to all causes. The intervention group showed statistically significant decreases in all these outcomes, as compared with the control group, thus indicating a broad benefit of the intervention in decreasing the risk of cardiovascular events and death due to all causes.

Moreover, the mean SBP in the intervention and control groups decreased by 30.9 mmHg and 7.8 mmHg, whereas the mean DBP decreased by 14.8 mmHg and 4.9 mmHg, respectively. The differences between groups in SBP and DBP were 23.1 mmHg (95% CI −24.4 to –21.9) and 9.9 mmHg (95% CI −10.6 to −9.3).

The results demonstrated the effectiveness and feasibility of implementing interventions led by village doctors to achieve target BP levels in poorly resourced villages, and may provide guidance for the development of government policies to allow trained village doctor-led interventions for uncomplicated hypertension in low- and middle-income countries, by using a standard protocol under supervision by physicians. This approach has the potential to significantly improve hypertension management and alleviate the burden of healthcare expenses, while increasing access to care for rural populations.

AHA 2022 has noted that this study empowered primary medical staff with enhanced capabilities through Chinese innovation, and the effects of the nearly 1% absolute risk reduction of primary outcome in the intervention group have notable implications for hypertension management in low- and middle-income countries worldwide with a high burden of hypertension.

The Chinese Heart-Healthy Diet on Hypertension—DECIDE-Diet Study

In 2017, an estimated 11 million deaths and 255 million disability-adjusted life years—a time-based measure that combines years of life lost because of premature mortality and time lived in states of less than full health or disability—were attributable to dietary risk factors [ 62 ]. Similarly, CVDs are significantly correlated with diets. Numerous studies have demonstrated that healthful diets [ 63 ], such as the Dietary Approaches to Stop Hypertension (DASH) diet and the Mediterranean diet, markedly decrease BP and CVD risk [ 64 – 67 ]. These diets emphasize the consumption of plant-based foods and olive oil, and limitation of red meat consumption. Despite the demonstrated health benefits of these diets, their implementation is often hindered by a perceived lack of flavor. Moreover, implementing Western-style diets in China, which has a high prevalence of CVDs, is challenging, because of the substantial differences in dietary patterns between Chinese and Western populations. Therefore, developing a healthful and palatable diet is imperative for the prevention and management of hypertension and CVDs in Chinese populations.

Circulation has reported the results of the Chinese Heart-Healthy (CHH) Diet pattern study, developed by Yangfeng Wu at the Peking University Clinical Research Institute [ 68 ]. A total of 265 patients with SBP of 130–159 mmHg participated in the Exercise and Cardiovascular Health-Diet (DECIDE-Diet) study, a single-blind randomized trial. After a 7-day run-in period, participants were randomized to either a normal diet or CHH diet. The CHH diet included four major Chinese cuisines—Shandong, Huaiyang, Cantonese, and Szechuan—tailored to the geographic locations of the participants, and included nonrepetitive dishes in a cycle of at least 2 weeks. In contrast, the normal diet was developed on the basis of commonly consumed local foods. During the 28-day intervention period, the study achieved a high rate of participant compliance: 97% of the participants completed the study and consumed an average of 97% of the meals provided.

The primary outcome was the change in SBP, which decreased by 5.0 mmHg (95% CI –6.5 to –3.5) in the normal diet group and 15.0 mmHg (95% CI –16.5 to –13.5) in the CHH diet group after 28 days. The differences observed for SBP and DBP between groups were 10.0 mmHg (95% CI –12.1 to –7.9) and 3.8 mmHg (95% CI –5.0 to –2.5).

Moreover, both diets were generally well received by participants, and the decrease in SBP by 1 mmHg cost only an additional CNY 0.4 (USD 0.06) per day. The author further estimated that adherence to the CHH diet was associated with a 20% decrease in CVD, a 28% decrease in heart failure, and a 13% decrease in all-cause mortality, thus indicating the efficacy, palatability, and cost-effectiveness of the CHH diet. These findings may provide valuable guidance for the Chinese government and other nations in developing guidelines and policies associated with health management.

However, the study has several limitations including confounding factors, such as the relatively short intervention time; enrollment below anticipated goals; and the controlled design. First, the intervention period was short, lasting only 4 weeks. Consequently, limited evidence suggesting a sustained hypertensive effect in the long term was found. Second, because whole food analysis was not used to measure nutrient composition, the intake of relevant nutrient components could not be ensured in the CHH diet. Third, the intended enrollment goals were not achieved because of the effects of the COVID-19 pandemic. Given the controlled design of this study, the generalizability of its findings to real-world scenarios warrants further validation.

Effectiveness of the Endovascular Baroreflex Amplification Technique on Hypertension—CALM-FIM Study with Long-Term Follow-up for 3 years

Despite the availability of various antihypertensive medications, 86% of patients with hypertension continue to experience uncontrolled hypertension, thus increasing their risk of developing CVDs. Therefore, investigating novel antihypertensive techniques and their potential effects on BP management is critical. Stimulating baroreceptors can lower BP by activating sympathetic and parasympathetic nerves [ 69 ]. Two antihypertensive techniques have been developed: baroreflex activation therapy and endovascular baroreflex amplification (EBA). MobiusHD, an implant for the internal carotid artery, belongs to the EBA category; this modality decreases BP through passive mechanical stimulation of baroreceptors, rather than using electrical stimulation as in baroreflex activation therapy [ 42 , 70 , 71 ].

The Controlling and Lowering Blood Pressure With the MobiusHD–First in Man (CALM-FIM) study was a prospective, open-label trial to assess the effectiveness of implanted MobiusHD in the unilateral internal carotid artery in 47 patients with resistant hypertension.

The primary outcomes were the incidence of adverse events and changes in BP, 24-hour ambulatory BP, and antihypertensive medication use after implantation. The results of the 6-month follow-up, published in The Lancet , indicated that BP was lowered by 30/12 mmHg (95% CI −38 to −21/−17 to −8 mmHg), and ambulatory BP was lowered by 21/12 mmHg (95% CI −19 to −14/−16 to −7 mmHg) [ 72 ]. After 3 years, the BP decrease remained at 30/12 mmHg (95% CI −38 to −21/−17 to −8 mmHg).

Regarding safety outcomes, the occurrence of five serious adverse events, including hypotension (n=2), hypertension (n=1), vascular access complications (n=2), and two transient ischemic attacks, were observed within 30 days post-implantation. By 30 days post-implantation, six serious adverse reactions had occurred, including strokes (n=2), transient neurologic symptoms (n=1), hypertension (n=1), and hypotension (n=2).

The occurrence of these serious adverse events underscores the importance of continued monitoring and evaluation of the safety and effectiveness of this device. Although the adverse events observed in patients who underwent implantation of the MobiusHD device eventually resolved, the high incidence rate of these events has prompted concern regarding the safety of this method. Therefore, future studies should assess the long-term safety and efficacy of the MobiusHD device, to provide a more comprehensive understanding of its benefits and risks and to inform evidence-based clinical practice. The results were published in JACC Cardiovascular Intervention [ 73 ].

Although the CALM-FIM study demonstrated the efficacy of MobiusHD based on EBA, the study had several limitations. First, the study design lacked a control group, thus preventing accurate evaluation of the outcomes and adverse events associated with the treatment. Second, the study’s observational design had the potential for confounding factors such as the Hawthorne effects, placebo effects, and regression to the mean. Furthermore, the study did not use urine or blood tests to assess medication compliance, thus posing challenges in ruling out the influence of medication differences among participants.

Therefore, although the study has provided preliminary evidence of the efficacy of MobiusHD, further trials with a more rigorous design are necessary to evaluate the benefit-risk profile of this technique.

Characteristics of Primary Care Institutions Associated with Hypertension Awareness, Treatment, and Control—China PEACE-Million Persons Project

China’s primary medical and health care system consists of approximately 900,000 institutions and 3 million workers, and provides basic public health services on a nationwide scale. The quality of primary medical care is reflected by the awareness, treatment, and control rate of hypertension [ 74 ]. Over the past few years, China has implemented substantial investments and reforms to its primary care system, aimed at improving the quality of care provided. However, characteristics including financing methods, medical treatment patterns, and medical personnel capacity vary among regions [ 60 ], and the relationships between various characteristics of primary care institutions and the awareness, treatment, and control rates of hypertension remain unclear [ 75 ]. Understanding these relationships will be crucial for improving the quality of primary medical care and hypertension management in China’s primary care system.

Research conducted by Xi Li and Jiapeng Lu from Fuwai Hospital Chinese Academy of Medical Sciences enrolled 433 primary care institutions from the Million Persons Project, which selected sites in all 31 provinces of mainland China through a convenience sampling strategy, to demonstrate the diversity of geographic distribution and demographics, risk factor exposure, and disease patterns. Among these sites, 660,565 patients with hypertension 35–75 years of age who had lived in the selected area for at least 6 of the prior 12 months were included.

Data were collected through standardized face-to-face interviews conducted by trained personnel using electronic questionnaires with real-time logic-checking capabilities. Univariate analyses of each institution-level were conducted with T-test or ANOVA. Moreover, multi-level logistic models with all participant-level variables were established. Institution-level variables with P<0.05 were retained in the final model. All these analyses were performed in SAS statistical software.

The results of standardized rates for hypertension awareness (8.2% to 81.0%), treatment (2.6% to 96.5%), and control (0% to 62.4%) were reported, and 10% of the awareness rate, 21% of the treatment rate, and 12% of the control rate were ascribed to primary care institutions. Characteristics of primary care institutions conducive to hypertension management included bonuses associated with performance (treatment rate OR=1.39, 95% CI 1.07–1.80), referrals through the online system (treatment rate OR=1.41, 95% CI 1.14–1.73; control rate OR=1.17, 95% CI 1.03–1.33), a family doctor service pattern (awareness OR=1.13, 95% CI 1.00–1.28; control rate OR=1.30, 95% CI 1.15–1.46), and a high proportion of practitioners (awareness OR=1.04, 95% CI 1.01–1.08; treatment rate OR=1.08, 95% CI 1.02–1.14). In contrast, characteristics detrimental to hypertension management included governmental allocation of resources, financial problems affecting daily work, and salaries associated with the numbers of outpatients and inpatients. The results have been published in The Lancet Global Health [ 76 ]. Considering the current situation in China, the training of primary care physicians must urgently be enhanced to increase the proportion of licensed practitioners, improve coordination between superior and subordinate hospitals, establish a robust network referral system, and optimize the incentive mechanism of performance bonuses. These strategies may also be relevant and applicable to other countries facing similar challenges.

However, this study had several limitations. The time mismatch between participant data (obtained from 2014 to 2021) and institutional characteristics data (obtained from 2016 to 2017) might have introduced bias in the observed associations, particularly given that some new policies were issued after 2017. Moreover, focusing on institutional characteristics without adjusting for individual health-care seeking behaviors might also have influenced the results of the analysis. Furthermore, the primary care institution characteristics included in the analysis, such as physician access to the clinical practice guidelines, might not have been comprehensive. Together, these limitations might have led to underestimation or overestimation of the effects of specific characteristics on hypertension management in primary healthcare systems, and affected the reliability and generalizability of the findings. Therefore, further studies including qualitative in-depth interviews and randomized controlled trials to assess these features would be essential and informative. In conclusion, this study highlighted the critical roles of primary care institution characteristics in the quality of medical care, and identified potential avenues for improving hypertension management in primary healthcare systems.

Conclusions

Hypertension is the most common chronic non-communicable disease. The ten aforementioned clinical studies have offered valuable insights into the treatment and management of hypertension ( Table 1 ). However, notable challenges in the management of hypertension remain to be addressed and elucidated in further research, to support evidence-based medicine, and achieve well-treated, controlled, and managed hypertension.

Classification of Top Ten Breakthroughs in 2022 Clinical Studies of Hypertension.

Conflict of interests

The authors declare no conflicts of interest.

Citation Information

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Guideline-Driven Management of Hypertension: An Evidence-Based Update

Associated data.

Several important findings bearing on the prevention, detection and management of hypertension have been reported since publication of the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) Blood Pressure (BP) Guideline. This review summarizes and places in context the results of relevant observational studies, randomized clinical trials and meta-analyses published between January, 2018 and March, 2021. Topics covered include BP measurement, patient evaluation for secondary hypertension, cardiovascular disease (CVD) risk assessment and BP threshold for drug therapy, lifestyle and pharmacologic management, treatment target BP goal, management of hypertension in older adults, diabetes mellitus, chronic kidney disease, resistant hypertension, and optimization of care using patient, provider and health system approaches. Presenting new information in each of these areas has the potential to increase hypertension awareness, treatment and control which remain essential for the prevention of CVD and mortality in the future.

Introduction

Globally, high blood pressure (BP) is the leading risk factor for cardiovascular disease (CVD) morbidity and mortality. 1 In the United States, high BP ranks first among modifiable risk factors in population attributable CVD risk, accounting for the largest proportion of coronary heart disease (CHD), heart failure (HF) and stroke events. 2 In adults with hypertension, control of BP with antihypertensive medication reduces the risk of CVD and all-cause mortality. 3 , 4 Thus, hypertension is one of the most consequential and remediable threats to the health of individuals and society.

While BP lowering interventions can be used to prevent CVD events and mortality, this can only be achieved by preventing high BP and recognizing, treating and controlling hypertension. 5 The first step in managing hypertension is accurate diagnosis. Once hypertension has been confirmed, lifestyle modification and pharmacological treatment can be initiated to reduce BP and CVD risk. Titration of nonpharmacological and medication interventions to maximum tolerable effectiveness and long-term persistence with the treatment regimen are essential for optimal BP control and CVD risk reduction.

In the United States, progress in the quest to reduce population BP over the past several decades has been quantified as trends in hypertension awareness, treatment and control to an SBP/DBP <140/90 mm Hg. In an analysis of National Health and Nutrition Examination Survey (NHANES) data, hypertension (SBP ≥140 mm Hg, DBP ≥90 mm Hg, or taking antihypertensive medication) awareness and treatment increased significantly in all age groups between 1999-2004 and 2011-2016 (approximately 85 and 79%, respectively, for adults ≥65 years in 2011-2016). However, the improvements primarily occurred between 1999-2004 and 2005-2010. 6 Hypertension awareness and treatment rates in 2011-2016 were relatively high, providing limited opportunity for improvement. In contrast, NHANES analyses identify markedly suboptimal rates of BP control. 6 , 7 Among all adults with hypertension, the proportion with BP controlled to a systolic BP (SBP)/diastolic BP (DBP) <140/90 mm Hg increased from 31.8% in 1999-2000 to 48.5% in 2007-08, peaked at 53.8% in 2013-14, and then declined to 43.7% in 2017-18. 7 Among adults taking antihypertensive medication, the prevalence of SBP/DBP control to <140/90 mm Hg increased from 53.4% in 1999-2000 to 68.3 % in 2007-08, peaked at 72.2% in 2013-2014, and then declined to 64.8% in 2017-18, such that control rates in 2017-18 were similar to those in 2005-6. 7 From a public health perspective, the substantial reduction in BP control from 2013-14 to 2017-18 is alarming.

In December 2013, the panel members appointed to the eighth Joint National Committee (JNC-8) published a report recommending a higher BP goal (SBP/DBP <150/90 mm Hg) for adults ≥ 60 years compared with the 2003 JNC-7 recommended target (SBP/DBP <140/90 mm Hg). 8 , 9 A minority report from five of the 17 JNC-8 panel members warned that relaxation of the BP goal would reduce the intensity of antihypertensive drug therapy and level of BP control. 10 In March 2017, a clinical practice guideline from the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) also recommended initiation of antihypertensive treatment in adults ≥60 years with an SBP persistently ≥150 mm Hg to achieve an SBP <150 mm Hg, with the possibility of a lower initiation and target SBP of 140 mm Hg in those with a history of stroke, a transient ischemic attack, or other evidence of high CVD risk. 11 It is conceivable that the JNC-8 panel members and ACP/AAFP guideline reports may be responsible for the diminution in hypertension control. In November 2017, the American College of Cardiology (ACC)/American Heart Association (AHA) in partnership with nine other professional societies published a BP guideline that redefined hypertension as a persistent average SBP ≥130 mm Hg or DBP ≥80 mm Hg (SBP ≥ 130 mm Hg for those ≥ 65 years of age), lowered the drug treatment threshold to an average SBP ≥ 130 mm Hg or DBP ≥80 mm Hg for adults with a 10-year atherosclerotic CVD (ASCVD) risk ≥10% and reduced the SBP/DBP goal of therapy to <130/80 mm Hg (SBP<130 mm Hg for those ≥ 65 years). 12 These changes were prompted by data showing an approximately 2-fold increase in CVD events and mortality in adults with BP 130-139/80-89 mm Hg compared to those with normal BP (<120/80 mm Hg), attributable risk estimates that this category of BP accounts for more than 20% of the BP-related CVD events, the results of multiple randomized clinical trials [including the PREVER-Prevention Trial and the Systolic BP Intervention Trial (SPRINT)] and meta-analyses of trials showing reduced CVD events and death with goal BP <130/80 mm Hg. 12 While the ACP and AAFP 11 failed to endorse the 2017 ACC/AHA Guideline recommendations for a lower BP goal, the Guideline has been embraced by most professional societies with an interest in BP and by US governmental agencies, including the National Center for Health Statistics (NCHS) that oversees the NHANES. Adoption of the ACC/AHA recommendations has the potential to increase hypertension awareness, treatment and control, both by increasing the proportion of adults taking antihypertensive medication and by treatment intensification for those with BP levels above target.

A substantial worldwide decline in population BP has occurred since the initiation of hypertension prevention, detection, treatment and control programs in the 1960s and 70s. 13 These BP reductions have been noted in high risk, socioeconomically disadvantaged populations, including in the Southeastern region of the United States, where population SBP levels declined by as much as 18 mm Hg over a 40 year period. 14 This seems to have resulted from a downward shift in average BP across the entire distribution of BP, suggesting an effect of lifestyle changes in addition to pharmacologic antihypertensive treatment.

This review focuses on the prevention, detection and management of hypertension with emphasis on new information since the publication of the 2017 ACC/AHA BP Guideline 12 .

BP Measurement and the Diagnosis of Hypertension

The ability to measure BP accurately remains a major challenge for providers managing patients with hypertension. Office BP measurements for clinical care are meant to be similar to those utilized in the observational cohort studies that have documented risk at a given BP level and the antihypertensive clinical outcome trials that have documented the benefit of BP lowering. 12 , 15 However, the time required for staff training and the need for efficiencies in provider workflow patterns continue to compromise the validity of office BP measurements used for diagnosing hypertension and assessing success in achieving hypertension treatment targets. 15 , 16

The 2017 ACC/AHA BP Guideline supports use of oscillometric devices to obtain automated office BP (AOBP) measurements and recommends out-of-office BP readings to confirm high BPs in the office, and to recognize masked hypertension (MH) and white coat hypertension (WCH). 12 The European Society of Hypertension recommended out-of-office BP in 2007 as a complement to office BP measurement. 17 The National Institute for Health and Care Excellence (NICE) clinical guideline in 2010 was the first to recommend confirmation of the hypertension diagnosis using out-of-office measurements, although this was primarily to exclude overtreatment of patients with WCH. 18 Since the publication of the 2017 ACC/AHA Guideline, other national guidelines have also recommended the use of out-of-office readings to exclude WCH and MH, though these readings were recommended to be complementary rather than preferred to office readings. 19 , 20 Differences between office BP, AOBP, HBPM and ABPM are summarized in Supplemental Figure I .

AOBP monitors that can be programed to measure multiple BP readings automatically after the recommended rest period were also promoted by the 2017 ACC/AHA Guideline and 2019 AHA Scientific Statement. 12 , 15 While earlier data suggested that BP varied with the presence or absence of staff during BP measurement with these devices, 21 more recent studies have refuted this concern when the core recommendations for accurate measurement are respected. 22 – 24 However, less active staff involvement can result in less staff time per reading compared to manual measurement (and potential cost savings). 25 A challenge to the use of oscillometric devices in place of mercury and aneroid sphygmomanometers in clinical practice and research is the lack of independent validation of many such devices and the lack of requirement for validation of devices sold in most countries, including the US. 15 , 26 Unfortunately, only 1 in 5 automated devices are validated for accuracy. 27 Online listing of validated devices, including the newly released U.S. Blood Pressure Validated Device Listing are now readily available. 28 , 29 Although well-designed comparisons of ABPM and HBPM are not available, some helpful reports have been published during the last two years. In a study of participants (N=333) with office BP < 140/90, ABPM was more sensitive in detecting MH than HBPM, with a MH prevalence of 25.8% overall and 11.1% at home, with 29-29.5% showing MH by both techniques. 30 In another study, HBPM was as effective as ABPM in predicting left ventricular mass index. 31 A comparison of office and out-of-office BP measuring techniques is shown in Table 1 .

Comparison of Office BP, Automated Office BP, ABPM and HBPM

ABPM, ambulatory blood pressure monitoring; BP, blood pressure; CVD, cardiovascular disease; HBPM, home blood pressure monitoring; LVH, left ventricular hypertrophy; MH, masked hypertension; NH, nocturnal hypertension; WCH, white coat hypertension.

Despite its lower sensitivity in detecting MH, HBPM remains the most practical option for recognition of MH and WCH as well as for BP monitoring, especially during medication titration and monitoring of treatment BP levels. However, careful attention to patient education is required in order for providers to have confidence accepting HBPM data over office readings to determine BP control ( Table 2 ). 12 , 32 , 33 In a study of community-dwelling adults (N=318), two readings taken in the morning and evening for a minimum of 3 days have proven sufficient for reliable estimation of out-of-office BP and for confirming the diagnosis of hypertension. 34 HBPM has been particularly useful with the increasing need for virtual visits to manage hypertension during the COVID-19 pandemic.

Procedures for Use of HBPM *

Note: We encourage training and certification through PAHO or AHA/AMA Target BP virtual courses.

AHA, American Heart Association; AMA, American Medical Association; BP, blood pressure; HBPM, home blood pressure monitoring; PAHO, Pan American Health Organization.

Newer technologies for BP measurement that are less intrusive and provide a more complete profile of BP are on the horizon. 35 These will require both validation for accuracy and their capacity to predict clinical outcomes. The ability to measure and compare central to brachial BP was proposed as a better way to predict CVD risk. 36 However, a recent study in a large cohort (N = 13,461) suggested that measurement of central BP using the Sphygmocor device was no more predictive of CVD outcomes than AOBP readings obtained with the Omron 907 device. 37

Patient Evaluation: Screening for Secondary Hypertension

The 2017 ACC/AHA Guideline provides detailed guidance on historical, physical and laboratory features that may suggest secondary hypertension and merit additional testing. 12 It is particularly important to consider an evaluation for secondary causes when the patient is young or the hypertension is resistant to treatment. Identification of a secondary cause may cure hypertension, or improve BP control if a cure is not feasible. The approaches to management of renovascular hypertension and primary aldosteronism have recently been modified.

Renovascular hypertension

Several randomized controlled trials (RCTs) of renal artery interventions in ASCVD renovascular hypertension have failed to demonstrate an improvement in mortality or renal survival 38 . A recent systematic review of 8 major RCTs reported reduction in DBP and the number of antihypertensive medications needed, but no differences in SBP or renal function after angioplasty. 39

Even when significant ASCVD renal artery stenosis is confirmed, the optimal course of treatment is not clear, particularly with unilateral lesions. 40 In most cases, unilateral lesions can be managed using medical therapy (renin-angiotensin system blockade) with periodic surveillance to ensure adequate perfusion of the contralateral non-stenotic kidney. However, for some patients, particularly those who are younger, have sudden onset of hypertension or have radiologic features that suggest fibromuscular dysplasia (FMD), direct intervention is often sensible ( Table 3 ). 41 For FMD this should consist of angioplasty without stents, whereas stents are needed for most atherosclerotic lesions to maintain long-term patency. For patients with bilateral hemodynamically significant stenosis, defined as a stenosis greater than 75%, intra-arterial intervention should be considered with careful assessment of patient risk for complications, especially renal athero-embolic events. In patients at high risk for complications from intra-arterial intervention, a trial of renin-angiotensin system blockade is an appropriate first step with careful monitoring of kidney function. If creatinine rises more than 30% or the patient develops sudden (flash) pulmonary edema, this will suggest the need for an invasive approach. Patients with severe bilateral stenosis were not included in the RCTs and require careful individualized decision-making with consideration of intervention to preserve kidney function.

Clinical Approaches to Renovascular Hypertension Evaluation and Treatment

CT, computerized tomography; CVD, cardiovascular disease; MR, magnetic resonance; US, ultrasound.

Primary aldosteronism

New evidence suggests that primary aldosteronism is part of a spectrum of aldosterone excess states. Recent publications suggest aldosterone excess plays a role in primary hypertension or intermediate conditions of relative aldosterone excess, a forme fruste of the full primary aldosteronism state. Data from Brown et.al. 42 support consideration of primary aldosteronism even when the plasma aldosterone/renin ratio (ARR) screening test is negative. In an analysis of patient cohorts at 4 centers, including participants with normal BP, untreated stage 1 and stage 2 hypertension, and treated resistant hypertension (RH), ARR was compared to urinary aldosterone excretion measured after oral salt loading. Using a urinary aldosterone level > 12 ug/24h as the threshold for diagnosis, primary aldosteronism was present in 11.3% of normotensive patients, and up to 22% of those with hypertension, with increasing prevalence associated with greater severity of hypertension. The ARR had poor sensitivity and negative predictive value, particularly when renin was suppressed. 42 Cohen et al. 43 reported very low (1.6%) utilization of ARR screening for patients with RH in the Veterans Administration system suggesting that many cases of primary aldosteronism are missed. These findings suggest that aldosterone excess may play a role even in primary hypertension and may be unrecognized as a contributor to RH ( Figure 1 ). For hypertensive patients with suppressed renin levels, especially those with uncontrolled or RH, it is important to go beyond the ARR to measure urinary aldosterone excretion under salt-loading conditions. Further, the concept of a spectrum of aldosterone excess mediated mechanisms may explain the effectiveness of mineralocorticoid receptor antagonists (MRAs) observed in the PATHWAY-2 trial of RH. 44

Schematic representation of the mechanisms of autonomous aldosterone production in primary hypertension. Aldosterone production from the adrenal zona glomerulosa is independent of the renin-angiotensin system and is not suppressible with dietary sodium loading. Excess aldosterone expands extracellular fluid volume by augmenting sodium reabsorption in the renal cortical collecting duct. Expanded fluid volume leads to hypertension and suppression of renin and the entire renin-angiotensin cascade. Increased aldosterone production is abnormal in the face of renin suppression but plasma aldosterone concentrations are lower than those of patients with classical overt primary aldosteronism. ACE, angiotensin converting enzyme; Ang, angiotensin; AT 1 , angiotensin type-1. Dashed line and grey tone indicates suppression.

CV Risk Assessment and BP Threshold for Drug Therapy

The 2017 ACC/AHA BP Guideline based decisions regarding initiation of medication on level of BP and estimation of ASCVD risk, supported by evidence from clinical trials and meta-analyses. 12 The ACC/AHA risk calculator provides guidance for patients age 40-79 years, but does not apply to younger patients where data are lacking. Based on average risk in the landmark antihypertensive drug trials, a 10-year ASCVD ≥10% was identified as the cut point for definition of high risk.

Treatment of hypertension in young adults

With rising rates of overweight and obesity, in the US and globally, the prevalence of hypertension and diabetes mellitus (DM) resulting from insulin resistance has increased and may carry greater risk in the context of multiple CVD risk factors, even in the young. 1 For young patients with isolated hypertension, lifetime risk of ASCVD is high. As the overall distribution of BP has shifted to a lower average value in the community, more CVD events are occurring at lower BP levels. 14 , 45 This was recently shown to be true for young adults with hypertension who have earlier onset of CHD, HF, stroke, transient ischemic attacks and peripheral arterial disease requiring intervention. In the Coronary Artery Risk Development in Young Adults (CARDIA) longitudinal study of 3851 young adults followed over a median of 18.8 years, only 4% were taking medication for hypertension. 46 Adjusted hazard ratios (HRs) for CVD events were 1.67 [95% confidence interval (CI), 1.01-2.77], 1.75 (95% CI, 1.22-2.53), and 3.49 (95% CI, 2.42-5.05), for elevated BP, and ACC/AHA stage 1 and stage 2 hypertension, respectively, compared to controls with normal BP. 46 Supplemented by evidence for target organ damage (TOD) including LVH 47 and brain volume and white matter changes 48 , high BP in the young may no longer be considered benign. Therefore, it may not be appropriate to delay antihypertensive pharmacologic treatment, even while lacking event-based RCT evidence for prevention of ASCVD. Young patients are reported to have lower awareness, slower time to diagnosis and poorer BP control than older patients. Concerns raised by providers relate to labeling of young adults with illness, medication safety concerns, especially in women of childbearing age, concerns related to potential misdiagnosis, and impact on life insurance rates. Both DBP and SBP are important for prediction of CVD risk in young adults. In a recently reported risk analysis conducted in almost 6.5 million Koreans, aged 20-39 years at baseline, who were followed for a median of 13.2 years, ACC/AHA stage 1 isolated systolic hypertension, isolated diastolic hypertension, and systolic/diastolic hypertension were associated with multivariate-adjusted hazard ratios of 1.36, 1.32, and 1.67, respectively, compared to normal BP. 49

The evidence suggests treatment of hypertension in the young using lifestyle modification with the addition of BP lowering medications when lifestyle interventions are inadequate. Allowing a period of 6 to 12 months to institute lifestyle modification is reasonable but only in the absence of TOD. There is an urgent need for hypertension treatment event-based RCTs in the young which will likely require measuring TOD endpoints rather than only CV events and death.

Lifestyle Management: The Cornerstone of Prevention and Treatment

Numerous environmental factors are associated with BP, especially components of diet, physical activity, and alcohol consumption. In many instances, changes in exposure to these factors has led to a corresponding change in BP, with the best proven interventions being a healthy diet, reduced sodium intake, weight loss, augmentation of potassium intake, physical activity, and abstinence or moderation in alcohol consumption. 12 , 50 These six interventions are effective for prevention of hypertension, treatment of hypertension, enhancing the effect of antihypertensive medication, and reducing the number of drugs needed to control BP ( Table 4 ).

Six Best Proven Nonpharmacological Recommendations for Prevention and Management of Hypertension.

DASH, dietary approaches to stop hypertension; SBP, systolic blood pressure.

A recent meta-analysis confirmed the efficacy of nonpharmacological interventions for prevention of hypertension in trials that were conducted in low- and middle-income countries. 51 Fu et al. 52 conducted a series of clinical trials network meta-analyses to estimate the comparative effectiveness of 22 different interventions for lowering BP in two groups of adults (those with an SBP ≥140 mm Hg, DBP ≥90 mm Hg, or taking antihypertensive medication, and those with an SBP 120-139 mm Hg or DBP 80-89 mm Hg). Based on the BP lowering effects in pooled analyses and the GRADE estimated quality of the underlying data 53 , they concluded that an intervention based on the Dietary Approaches to Stop Hypertension (DASH) was superior to usual care and all other nonpharmacological interventions in lowering SBP. Unfortunately, differences in study design, intervention methods, the samples studied, and other aspects of the clinical trials that were compared make it difficult to conduct a fair comparison. The greatest impediment to accepting the conclusion that the DASH diet provides superior BP lowering compared to the other interventions recommended in the 2017 ACC/AHA Guideline is that the DASH diet trials included in the Fu et al. 52 meta-analyses were feeding studies, whereas most of the other interventions were evaluated in trials that employed behavior change interventions. Feeding studies provide a very efficient means to change diet but they are expensive and the efficacy in such studies is not generalizable. In clinical practice, behavior change and pill supplementation are the only practical approaches to implementing nonpharmacological recommendations, with behavior change being the preferred approach. 12 In a three-arm behavioral change trial (N = 810; baseline mean SBP/DBP = 134.9/84.8 mm Hg), that compared usual care, an “established” BP lowering intervention (weight loss, sodium reduction, increased physical activity, and limited alcohol intake), and addition of the DASH diet to the “established” intervention, both active interventions were effective compared to usual care (approximately 4 mm Hg SBP net difference), but addition of the DASH diet to the “established” diet provided no additional statistically significant lowering of SBP (P = 0.43). 54 It may be better to accept that each of the nonpharmacological interventions recommended in the 2017 ACC/AHA Guideline is effective and use of two or more interventions is likely to result in a more substantial effect. 55 Likewise, each of the interventions has greater efficacy at higher starting levels of BP. A pragmatic approach in clinical and public health practice is to decide which of the proven interventions are likely to be of greatest benefit based on an individual’s or population’s lifestyle and their perceived willingness to embrace the interventions. Specifically, is overweight, excessive sodium or alcohol consumption, or unhealthy diet the biggest problem and which of the possible interventions is likely to be embraced with the most enthusiasm?

The greatest potential for a population-wide nonpharmacological intervention is gradual reduction in the addition of sodium during food processing and preparation. 56 Resolve to Save Lives, the World Health Organization, the World Hypertension League and others are collaborating to achieve the goal of sodium reduction globally. 57 – 60 A new biostatistical method, which facilitates aggregation of data from two-armed RCTs, the most common type of experimental contrast, has made estimation of the dose-response relationship between sodium and BP more feasible. 61 Filippini et al. 62 used this method to conduct a sodium-BP dose-response meta-analysis based on 81 clinical trials with a minimal duration of four weeks. They identified a substantially linear dose-response relationship between sodium intake and BP across the entire range of exposure, with a 100 mmol/d reduction in sodium being associated with a 5.43 mm Hg reduction in SBP. The results were similar for those with or without hypertension, except that the former group exhibited a steeper decrease in BP following sodium reduction. These findings support the lower sodium intake target (<1,500 mg/d) recommended by the AHA 63 , compared to the <2,300 mg/d target endorsed by the 2019 National Academies of Sciences, Engineering, and Medicine Dietary Reference Intakes Review Committee 64 , or the <2,000 mg/d target advocated in 2012 by the World Health Organization. 65 However, the findings also suggest benefit from any reduction in sodium intake that can be achieved.

In a separate analysis of 32 RCTs, Filippini et al. 66 reported a U-shaped pattern for the dose-response relationship between potassium intake and BP, with the optimal BP lowering effect occurring for potassium intakes in the range of 90-150 mmol/d. The BP lowering effect was greater in participants with compared to those without hypertension and for those at higher levels of sodium intake.

Several reports have confirmed the errors associated with use of spot urines to estimate 24-hour urinary sodium intake. 67 – 70 Spot urines provide systematically biased estimates of 24-hour urinary excretion, with over-estimation at lower intakes of sodium and under-estimation at higher intakes. 67 Likewise, use of spot urines to estimate 24-hour urinary sodium intake yields a J-shaped relationship with mortality whereas the relationship is linear when 24-hour urine collections are used to assess the relationship. 67 The World Hypertension League published a position paper on use of spot urines, short duration timed collections, and 24-hour collections to assess dietary sodium intake. 71 The position paper endorsed use of a single 24-hour urine measurement over a series of days from a representative population sample for estimation of a population’s current 24-hour dietary sodium ingestion and an average of at least three non-consecutive 24-hour urinary collections was recommended for estimation of current usual dietary sodium intake in individuals. Despite the well-documented errors resulting from use of spot urines to estimate average intake of dietary sodium, leading peer-reviewed journals continue to publish manuscripts in which dietary sodium intake has been estimated using spot urines. 72 – 74

Pharmacological Management

The 2017 ACC/AHA Guideline and other recent guidelines continue to recommend thiazide or thiazide-type diuretics, calcium channel blockers (CCBs), angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) as initial drug choices, and for subsequent add-on therapy, based on their efficacy in reducing BP and documented benefit in reducing clinical outcomes. 12 , 19 , 75 Beta-blockers are generally not recommended as first line agents in patients without CHD or heart failure due to lesser benefit on stroke reduction compared with agents from the other recommended classes. 12 , 20 , 75 , 76 Spironolactone or eplerenone are recommended for BP control in patients with RH. 12 , 77

Chlorthalidone and indapamide, thiazide-like diuretics, have a longer duration of action compared to thiazide diuretics and are the preferred diuretics for management of hypertension. HCTZNetwork meta-analyses have shown benefit of chlorthalidone over HCTZ on clinical outcomes, although a large (N=730,225) retrospective, non-randomized observational study of new users of chlorthalidone (N=36,918) compared to HCTZ from administrative databases failed to document a significant difference in effectiveness. 78 The VA Diuretic Comparison Project, a randomized comparison of chlorthalidone and HCTZ effects on clinical outcomes in 13,500 patients, is scheduled for completion by the end of 2022. 79

Some glucose lowering agents, particularly glucagon-like peptide-1 (GLP-1) receptor agonists and sodium glucose cotransporter-2 (SGLT-2) inhibitors significantly improve CVD and kidney outcomes, especially in diabetic patients with and without hypertension. They also reduce BP significantly, with SGLT-2 inhibitors seeming to have the largest effect. 80 , 81 The magnitude of BP lowering (2-4 mm Hg on 24 hour ABPM) with these agents is less than with most first-line antihypertensive agents. Given this and their greater cost, SGLT-2 inhibitors should be prescribed primarily for glucose lowering rather than for treatment of high BP.

Despite the lower BP targets recommended in the 2017 ACC/AHA Guideline, hypertension control rates in the US remain suboptimal even by the higher JNC-7 BP treatment targets, largely due to under-treatment, especially in Black patients. 82 Quality improvement interventions have increased BP control overall and in race-ethnic subgroups, but a 5-10% difference in control rates persists between Black and non-Black adults. Clinician inertia and patient nonadherence to the prescribed treatment continue as major contributors to inadequate BP control. A recent report from a quality improvement project aimed at more accurate BP measurement, reducing therapeutic inertia, and increasing treatment adherence over 6 months demonstrated sustained SBP lowering of 12.7 mm Hg for an additional 6 months compared to a 5 mm Hg SBP decline during the baseline period in patients with uncontrolled BP, P<0.0001. 83 However, clinician inertia was only reduced from 52% to 49.5%. No race/ethnic difference in BP control was noted with the BP regimen utilized in the SPRINT even in the < 120 mmHg arm where chlorthalidone, the primary diuretic, and amlodipine, the primary CCB, were provided at no cost to the study participants. 84 The effectiveness, safety, and cost-effectiveness of 90 compared to 30 day prescription refills in improving adherence has also been demonstrated. 85 The major elements of an effective antihypertensive drug treatment program are provided in Table 5 .

Keys to Effective Blood Pressure Control in Adults with Hypertension

RCTs have demonstrated that the risk of CVD can be greatly reduced with effective antihypertensive therapy. 3 , 4 Choice of an optimal goal for BP treatment should be based on a balance between the best level for CVD prevention and the risk of untoward side effects resulting from the treatment.

On the basis of new evidence, the 2017 ACC/AHA Guideline reduced the SBP/DBP goal from that recommended in the 2003 JNC-7 [<140/90 mm Hg for most adults but <130/80 mm Hg for those with DM or chronic kidney disease (CKD)] to <130/80 mm Hg for most adults but an SBP <130 mm Hg for noninstitutionalized ambulatory community-dwelling adults ≥65 years of age. 12 Evidence supporting this guideline change included results of the SPRINT as well as multiple systematic reviews and meta-analyses, as summarized in several post-guideline reports. 86 – 88 In addition, a recent direct meta-analysis by Sakima et al. 89 , restricted to 19 trials in which adults with hypertension were randomly assigned to a different BP target, reported a significant reduction in major CVD events, MI and stroke in those assigned to more versus less intensive treatment and in subgroup analysis identified a BP target of < 130/80 mmHg as optimal for CVD protection. Likewise, a meta-analysis of four RCTs conducted in patients with prior stroke documented a significant reduction in recurrent stroke among those randomized to more intensive BP reduction. 90

Concerns have been raised that the CVD and all-cause mortality benefit of intensive BP control in the SPRINT might have been offset by an increased rate of treatment adverse effects. This concern was largely assuaged by the recent demonstration that intensive BP control is not associated with other causes of hospitalization. 91 Another widespread concern, especially in older adults, had been that more intensive antihypertensive treatment might increase the frequency and/or severity of orthostatic hypotension, leading to falls, syncope and/or CVD events. This concern was put to rest by two reports by Juraschek et al. 92 , 93 examining the SPRINT data and the aggregated individual patient data from multiple clinical trials for association of intensive treatment with orthostatic hypotension. In the SPRINT, orthostatic hypotension was more common in the standard treatment group and was not associated with a higher rate of CVD events or with syncope, electrolyte abnormalities, injurious falls or acute renal failure. 92 , 94 In the Juraschek et al. 93 meta-analysis of 18,466 participants, including those in the SPRINT, intensive BP lowering treatment also reduced the risk of orthostatic hypotension, possibly due to improvement in baroreflex function and diastolic filling while reducing left ventricular hypertrophy and/or arterial stiffness. Thus, asymptomatic orthostatic hypotension during hypertension treatment should not trigger automatic down-titration of therapy, even in the setting of a lower BP goal.

The AHA’s Life’s Simple 7 focuses on cardiovascular health factors for primordial or primary prevention of CVD (smoking, body mass index, physical activity, total cholesterol, diet, BP and fasting glucose). 95 , 96 The AHA Life’s Simple 7 online survey tool increases patient awareness of their BP and other related comorbidities such as DM, obesity and high sodium intake. 97 . Treating hypertension to goal aims to achieve ideal cardiovascular health.

Older Adults

Professional societies provide conflicting advice on best practices for management of hypertension in older adults. The 2017 ACC/AHA Guideline recommends a treatment goal of <130 mm Hg for noninstitutionalized ambulatory community-dwelling older adults (≥65 years of age) and an individualized team-based approach, based on clinical judgement and patient preference, for those with a high burden of comorbidity and limited life expectancy. 12 In adults at high risk for CVD, including older adults, Hypertension Canada 2020 recommends initiation of antihypertensive medication in those with an SBP ≥130 mm Hg and treatment to an SBP goal <120 mm Hg. 98 The National Heart Foundation of Australia hypertension guideline recommends initiating antihypertensive drug therapy in “patients at moderate absolute CVD risk (10-15% 5-year risk) with persistent BP ≥140 mm Hg and/or ≥90 mm Hg diastolic” and an initial SBP/DBP target of <140/90 mm Hg or lower, if tolerated, with an SBP goal of <120 mm Hg in older adults (>75 years), if tolerated. 99 At the other extreme, the American College of Physicians (ACP) and American Academy of Family Physicians (AAFP) recommend that adults ≥60 years with a persistent SBP ≥150 mm Hg should be treated with antihypertensive medication to achieve a target SBP of <150 mm Hg, with consideration of a <140 mm Hg target in those with a history of stroke, transient ischemic attack, or other unspecified evidence of high risk for CVD. 11

Population modeling studies 100 , 101 have suggested substantial health benefits from implementation of the 2017 ACC/AHA Guideline recommendations compared with those in the 2003 JNC 7 Report 9 or the 2014 JNC-8 Panel Members Report 8 . In US adults ≥40 years, Bundy et al. 100 estimated that in comparison to the 2014 JNC-8 Panel Members Report recommendations, implementation of the 2017 ACC/AHA Guideline recommendations would result in an annual reduction of 340,000 CVD events and 157,000 deaths ( Table 6 ). In an analysis confined to adults ≥60 years, Jaeger et al. 102 identified a high 10-year risk of ASCVD (18.0%) in adults for whom the ACC/AHA but not the ACP/AAFP Guideline recommends antihypertensive drug therapy. Among adults already taking antihypertensive medication, the 10-year risk of ASCVD in those recommended intensification of therapy by the ACC/AHA, but not the ACP/AAFP, was also high (18.2%). Thus, the ACC/AHA Guideline is more effective than the ACP/AAFP Guideline in identifying adults ≥60 years of age at high CVD risk for the initiation and intensification of antihypertensive drug therapy.

Simulation study by Bundy et al. 100 comparing estimated annual prevention of CVD events and deaths by adhering to 2014 JNC-8 panel recommendations or the 2017 ACC/AHA BP Guideline.

Note: Sensitivity analysis determined that, even if 100% implementation of the 2017 guideline were not achieved, the CVD event and death reductions would still be significantly larger compared to the 2014 guideline. ACC, American College of Cardiology; AHA, American Heart Association; ARCS, Atherosclerosis Risk in Communities Study, BP, blood pressure; CV, cardiovascular; CVD, cardiovascular disease; JNC, Joint National Committee; MESA, Multi-Ethnic Study of Atherosclerosis Study; NHANES, National Health and Nutrition Examination Survey; NNT, number needed to treat; RCT, randomized controlled trial.

During the past two years, several additional original research papers and meta-analyses have contributed to our understanding of the management of hypertension in older adults. 103 – 106 In an analysis of the overall SPRINT cohort [N=9361; mean age=67.9 years; median follow-up (FU) = 3.34 years], mild cognitive impairment (MCI) was detected in 239 of the 4678 participants (16.2 per 1000 person-years) randomized to intensive antihypertensive treatment (SBP target <120 mm Hg) compared with 284 of the 4683 participants (19.4 per 1000 person-years) randomized to standard antihypertensive treatment (SBP target <140 mm Hg), resulting in a HR (95% CI) of 0.83, 0.70 – 0.99. 103 In a randomized comparison of participants with a median FU of 5.11 years (trial and extended post-trial FU), there was a significant difference in both MCI (HR, 95% CI = 0.81, 0.69 – 0.95; P = 0.007) and the composite of dementia and MCI (HR, 95% CI = 0.85, 0.74 – 0.97; P = 0.01), and a nonsignificant trend for benefit in dementia per se (HR, 95% CI = 0.83, 0.67 – 1.04). 103 During FU, CVD events occurred much earlier than dementia indicating the need for trials with a longer period of treatment and FU than occurred in the SPRINT where the trial was stopped prematurely due to CVD and all-cause mortality benefit after a median FU of only 3.26 years.

In a subset of 670 SPRINT participants (mean age = 67.3 years) who were evaluated with brain magnetic resonance imaging (MRI) at baseline and after four years of FU (N = 449), randomization to intensive treatment was associated with a smaller increase in cerebral white matter lesion volume, an independent risk factor for cognitive decline and dementia, compared to standard treatment during trial FU. 104 Similar apparent MRI benefits were noted in the INFINITY trial and during extended FU in the ACCORD trial. 105 , 106

In a secondary analysis, confined to SPRINT participants who were ≥80 years at baseline (N = 1167; mean age = 83.5 years), those randomized to intensive and standard treatment achieved a mean SBP of 123.9 mm Hg and 135.3 mm Hg, respectively, resulting a somewhat smaller mean difference between the two groups (11.5 mm Hg) 107 than the average difference (14.8 mm Hg) noted in the overall trial cohort (N = 9361). 94 , 103 Despite this and the smaller sample size, randomization to intensive treatment lowered the risk of major CVD events (HR, 95% CI = 0.67, 0.50 – 0.90), all-cause mortality (HR 0.67, 95% CI 0.48 – 0.93), and MCI (HR 0.72, 95% CI 0.53 – 0.98) compared with standard treatment. 107 The CVD and mortality benefits resulting from intensive therapy were similar to those reported in an earlier subgroup analysis confined to participants ≥75 years (N = 2636). 108 In the SPRINT participants ≥80 years, there was no evidence that gait speed modified the treatment effect on major CVD events or all-cause mortality, but the participants with higher baseline Montreal Cognitive Assessment (MoCA) scores experienced significantly better CVD and all-cause mortality outcomes compared to their counterparts with lower MoCA scores (0.01 and 0.003, respectively). 107

In a meta-analysis that included 14 RCTs (N = 96158; mean age = 69 years), BP lowering (12 trials; N = 92,135; mean FU = 4.1 years) resulted in a small but significant reduction in the risk of dementia or cognitive impairment [odds ratio (OR), 95% CI: 0.93, 0.88 – 0.98). 109 There was no convincing evidence for the superiority of any class of antihypertensive medication in the prevention of dementia or cognitive decline in a meta-analysis of 21 cohort studies (N = 43,049) and eight clinical trials (N = 13,817), two of which were treated as cohort studies in the analysis, where the mean age of most participants was between 70 and 79 years. 110

Several ongoing SPRINT-like RCTs are being conducted in Brazil and China in patients with hypertension and diabetes and with hypertension and stroke. 111 These trials are utilizing study designs that allow for continued treatment and trial assessment of dementia should a convincing difference in CVD events occur prior to the planned end of the trial. Collectively, they will contribute to our understanding of the optimal SBP treatment target for prevention of CVD, all-cause mortality, MCI, and dementia, overall and in subgroups, including in older adults.

Diabetes Mellitus (DM)

High BP and type 2 DM frequently coexist, with hypertension being reported in approximately 80% of patients with DM. In cohort studies, the combination of hypertension and DM has been repeatedly shown to dramatically increase the risk of CVD compared to either risk factor on its own. 112 Lifestyle modification is central to prevention and management of both DM and hypertension, with an emphasis on weight loss and physical activity for prevention and control of DM. 113 , 114 Addition of antihypertensive drug therapy is recommended because most patients with the combination of hypertension and DM are at high risk for ASCVD. 12 In addition, most surveys suggest that clinicians do not formally estimate CVD/ASCVD risk even when recommended by guidelines. 115 The benefits of antihypertensive drug therapy for management of hypertension in patients with DM have been extensively demonstrated in individual RCTs and meta-analyses of clinical trials. 3 , 116 All recommended classes of antihypertensive drug therapy, including diuretics, are similarly effective for prevention of CVD, except in those with heavy proteinuria and/or advanced kidney disease where renin-angiotensin system inhibitors are indicated. 12 Typically, a combination of two or three agents is required to achieve BP targets.

There is substantial guideline concordance for an SBP goal of <130 mm Hg in most adults with hypertension and DM. 12 , 19 , 117 For example, in 95.7% of adults on antihypertensive medication who remain above their recommended BP goal both the ACC/AHA BP Guideline and American Diabetes Association (ADA) Position Statement recommend intensification of therapy. 118 The Action to Control Cardiovascular Risk in Diabetes BP Trial (ACCORD BP) was based on a factorial design, in which the planned analysis assumed no interaction between the different treatments being studied (BP lowering and glycemic control). 119 The ACCORD BP results indicate this assumption was not realized, with the consequence that the planned analysis yielded results that are unreliable. 119 In a secondary post hoc analysis, the participants randomized to intensive BP lowering (SBP target <120 mm Hg) and standard glycemic control derived CVD prevention benefits that were comparable those seen with intensive BP lowering in the SPRINT. 120 There was no evidence of CVD benefit in the participants randomized to intensive BP lowering and intensive glycemic control. However, after the intensive glycemic intervention was discontinued, due to harm, CVD prevention in those randomized to intensive BP lowering changed to a pattern like that seen in SPRINT. 120 In a secondary analysis of 10,948 Action in Diabetes and Vascular Disease (ADVANCE) RCT participants, all of whom had DM at baseline, treatment with a perindopril-indapamide combination significantly reduced mortality and major CVD (macrovascular and microvascular) events compared to placebo, irrespective of baseline SBP or a 10-year ASCVD risk <20% or ≥20%. 121 In those with a baseline SBP <140 mm Hg, most of the active therapy benefit resulted from treatment in the group with a baseline SBP 130-139 mm Hg – a finding that supports the 2017 ACC/AHA Guideline recommendation to treat such individuals with a combination of nonpharmacological therapy and antihypertensive medication, especially those with a 10-year ASCVD risk ≥10%. 12

Chronic Kidney Disease (CKD)

The inclusion and careful renal disease monitoring of patients with stage 3-4 CKD in the SPRINT has expanded our understanding of the kidney function changes that occur with intensive BP control. Subgroup analysis yielded similar benefits for prevention of CVD and all-cause mortality compared to what was identified in the full cohort, with very low rates of the main renal endpoint in those with CKD at baseline (halving of eGFR or development of ESRD). When lesser degrees of kidney function decline were considered, there was a higher risk of ≥ 30% decline in eGFR and lower albumin excretion rates with intensive therapy compared to standard therapy reported for both patients with and without CKD at baseline. Intensive treatment was associated with higher rates of reported acute kidney injury serious adverse events. 122 , 123 However, additional analyses suggest these changes were hemodynamic and were not associated with urinary biomarkers of kidney damage which were lower in the intensive treatment group. 124 Similar findings were reported for a sub-study of ACCORD participants. 125 These results which support a benign hemodynamic process rather than permanent injury as the mechanism for a rise in serum creatinine remain preliminary, covering only the first 1-2 years of treatment; thus, additional longer term data will be needed to confirm the findings.

An updated Kidney Disease Improving Global Outcomes (KDIGO) BP guideline has been released. 126 The report recommends standardized office BP measurements, preferably using an automated device, and intensive antihypertensive therapy with a target SBP of <120 mm Hg for all patients with CKD not on dialysis, including those with and without DM.

Resistant hypertension

Resetting the general BP goal for antihypertensive therapy to <130/80 mm Hg by the 2017 ACC/AHA guideline de facto changed the definition of treatment RH. 12 This change was reconfirmed by the 2018 AHA Scientific Statement on RH 77 which formally defined the disorder as BP that remains uncontrolled above goal in spite of the concurrent use of 3 antihypertensive drugs of different classes. These pharmacologic classes commonly include a long-acting CCB, a blocker of the renin-angiotensin system (ie. ACEI or ARB) and a diuretic, and all 3 agents should be administered at maximum or maximally tolerated doses and at the appropriate dosing interval. RH also includes patients whose BP is controlled at or below goal but requiring ≥4 antihypertensive agents of different classes to achieve target. 77

A critical change in the definition of RH in the 2018 AHA Scientific Statement was that pseudo-resistance (ie. error in BP measurement, the white coat effect and/or suboptimal adherence to the antihypertensive drug regimen) now must be excluded before a patient can be labeled as having RH. 77 Exclusion of pseudo-resistance before making the diagnosis of RH was also recommended by the 2018 European Society of Cardiology (ESC)/European Society of Hypertension (ESH) BP guideline. 19 While the new goal for BP control in the office is now <130/80 mm Hg, it is important to remember that office BP should be confirmed using out-of-office measurements and that the 24-h ABPM goal is now <125/75 mm Hg as recently validated. 12 , 15 , 77 , 127

Under the new definition of RH using the 130/80 mm Hg cutoff, its prevalence was expected to escalate dramatically, placing an exponential burden on the healthcare system. However, population modeling studies have estimated that this change would result in only about a 2% increase in the prevalence of RH (from 17.7 to 19.7%) in the United States. 128

The importance of RH is its association with higher CVD and kidney disease risk compared to hypertension without resistance, but the prognosis of RH using the current definition had not been studied. 77 The first evidence was provided by a large RH cohort study from Korea (2000 participants) with the white coat effect excluded demonstrating that the risk for major adverse cardiovascular events (MACE; myocardial infarction, stroke, heart failure or CV death) and adverse kidney outcomes was similar under the 2018 AHA as compared with earlier definitions of RH with no significant difference for predicting MACE. 129

In addition to cardiac, central nervous system and kidney target organ damage, aortic stiffness had been demonstrated both as a pathogenetic factor and a consequence of the hypertensive process, but the prognostic importance of aortic stiffness in RH per se had not previously been evaluated. A large cohort study (891 participants) of patients with RH demonstrated that patients with increased aortic stiffness, as measured by carotid-femoral pulse wave velocity (cfPWV), had a significant 2.2- to 2.6-fold increased risk of CVD events and mortality. 130 Increased aortic stiffness predicted adverse cardiovascular outcomes and mortality and improved CVD risk stratification in RH. 130 Thus, cfPWV measurement might be considered in the work up and management of RH.

In the management of RH, it has heretofore been unclear which BP measurements optimally predict TOD and prognosis. A large cohort study (1726 participants) of RH has shown that ABPM seems to be more strongly associated with adverse CVD and mortality outcomes than clinic BP and that BP measured during follow up with patients on treatment was more strongly associated with adverse outcomes than baseline BPs. 131 Measurement of ambulatory rather than clinic BP, and on-treatment BP as opposed to baseline measurements, improved risk discrimination for prediction of adverse outcomes. Uncontrolled ABPM levels were associated with adverse outcomes, whereas office BP levels after adjustment for ambulatory BP were not. Furthermore, the previous and new lower BP cutoffs for RH were approximately equivalent in their strengths of association with adverse outcomes. These results encourage the use of serial ABPM in the management of patients with RH. 131

Both the 2017 ACC/AHA guideline and the 2018 AHA Scientific Statement on RH recommend comprehensive screening for secondary causes of hypertension in all patients with RH 12 , 77 . Primary aldosteronism has a particularly high (≈20%) prevalence in RH and is relatively easy to screen with an ARR. 77 , 132 At least 2 studies have confirmed the abysmal rates (1.6 - 2.1%) of screening for primary aldosteronism in RH. 43 , 133 Given the recent discovery of a higher prevalence of autonomous aldosterone production than previously recognized in primary hypertension 42 , the devastating CVD and renal consequences of primary aldosteronism beyond those for primary hypertension and the availability of specific treatment in the form of adrenalectomy for unilateral and MRAs for bilateral disease 132 , these studies uncovering poor detection effort provide a clarion call to increase screening for primary aldosteronism in RH, and indeed in all patients with hypertension.

The 2018 AHA Scientific Statement on RH presented a new evidence-based template for the therapeutic sequence, first recommending optimization of the 3 drug regimen (agent, dose and timing), followed by substitution of a thiazide-like diuretic (chlorthalidone or indapamide) for hydrochlorothiazide. 77 If BP remains uncontrolled, the Statement recommends addition of a MRA (spironolactone or eplerenone) on the basis of demonstrated superiority over other 4 th drug options in PATHWAY-2. 44 , 77 , 134 Beyond this recommendation, all others are expert opinion only.

The available MRAs each have potential problems in the treatment of RH. Spironolactone displays cross-inhibition of the androgen receptor resulting in reproductive hormone-related adverse effects, and eplerenone is less potent and has a shorter half-life requiring twice daily dosing to control BP. Esaxerenone is a non-steroidal, potent, selective MRA with the potential for fewer side effects. In a double-blind, large-scale RCT in patients with primary hypertension and normal GFR, esaxerenone was noninferior to eplerenone in lowering BP for 12 weeks. 135 Non-steroidal MRAs such as esaxerenone and finerenone have great potential in lowering BP in RH without inducing hyperkalemia, a potential adverse effect of steroidal MRAs, especially in adults with reduced GFR. Meanwhile, the AMBER trial has demonstrated that K + -binding agent patiromer can enable the use of spironolactone with less hyperkalemia in patients with RH and CKD. 136 As demonstrated by a secondary analysis of SPRINT, irrespective of the pharmacologic agents employed, intensive BP lowering is superior to standard treatment in terms of CVD outcomes in RH. 137

Optimization of Care Using Patient, Provider and Health System Approaches

Hypertension is a chronic disease process requiring accurate detection and lifelong management to maximize clinical outcomes. Optimization of hypertension care demands, first and foremost, affordable and sustainable access to care. This includes patient identification; patient and clinician agreement on the appropriate BP goal; shared decision-making that facilitates the patient’s benefit, goals and values; BP monitoring at both patient and practice levels; implementation of team-based care with defined team member roles; appropriate lifestyle recommendations and counseling; systematic follow up; minimization of clinician inertia in the initiation and intensification of treatment; promotion of a high level of adherence to the therapeutic regimen, and the use of electronic medical records, mobile health technologies, BP self-monitoring and telemonitoring, and other novel technologies. 5 Overall, governmental, health system, payor and community resources must be united and deployed to provide patient self-management support, health care delivery design, decision support and clinical information systems that, when integrated, result in informed, activated patients and prepared, anticipatory practice teams working together to improve care and outcomes. 5 , 138 , 139

Clinician therapeutic inertia, defined as suboptimal prescription of antihypertensive therapy, has been identified as a major barrier preventing patients with hypertension from achieving their guideline-recommended BP goals. The US National Ambulatory Medical Care Survey indicates that in 41.7 million primary care visits (2005-2012) in patients with SBP ≥140 mm Hg or DBP ≥ 90 mm Hg, new antihypertensive medication was only initiated in 7 million (16.8%). 140 , 141 Reasons for failing to initiate or intensify antihypertensive therapy include lack of time, workflow constraints, concern about side effects, lack of knowledge to make pharmacologic agent and/or dosing decisions and uncertainty about the patient’s out-of-office BP. Overcoming clinician inertia can be accomplished through an integrated health system model of care. For example, BP control rates exceed the national average in the Kaiser Permanente and Veterans Affairs health systems, where the approach to BP control is systematic. Identifying patients with hypertension, standardizing BP measurements, and using a stepwise treatment algorithm have led to an increase in BP control rates from 54% in 2004 to 84% in 2010 in the Kaiser Permanente Southern California health system. 142

Another major cause of uncontrolled BP is suboptimal adherence to the antihypertensive regimen, including failure to (1) initiate pharmacotherapy, (2) take medications as frequently as prescribed, and (3) persevere on therapy long-term. 143 Barriers to the achievement of a high level of adherence include limited access to care, cost, social determinants of health, complex medication regimens, inconvenient medication dosing and frequency, behavioral factors and adverse effects of medications in asymptomatic patients. While still a work in progress, detection of poor adherence ranges from simple, low cost screening tests in patients with uncontrolled BP to electronic and biochemical monitoring in those with RH. Consistently effective intervention strategies include increased patient-clinician communication, use of electronic communication methods, patient education and lifestyle and behavioral counseling. 143

One of the most important strategies to improve outcomes in the care of hypertension is team-based care, a multidisciplinary team surrounding the patient, to optimize the quality of care. The team includes the patient at the center, the primary clinician and other health professionals (eg. nurses, pharmacists, physician assistants, dieticians, lifestyle counselors, social and community health care workers) each with specifically designated responsibilities in care. These health care professionals complement the primary clinician by providing process support and sharing the responsibilities of care.

Several clinical trials on the effectiveness of team-based care are available, but their individual participant size has generally been too small to provide the statistical power necessary to demonstrate effectiveness in lowering BP. Comparative effectiveness of various implementation strategies in BP reduction in patients with hypertension was recently assessed in a systematic review and meta-analysis of over 100 trials in 55,920 patients. 144 Team-based care with medication titration by a non-physician resulted in lowering of SBP by 7.1 mm Hg (95% CI 8.9-5.2) and by a physician by 6.2 mm Hg (95% CI 8.1-4.2). Multilevel strategies without team-based care also significantly lowered SBP (by 5 mm Hg). At the patient level, health coaching reduced office SBP by 3.9 mm Hg and HBPM by 3.7 mm Hg. Multilevel, multicomponent implementation strategies with and without team-based care are the most effective methods of BP control among hypertensive patients. 144 Thus, implementation strategies targeting multilevel or patient level barriers to care are appropriate methods to control BP in hypertensive patients. With the evidence currently available, these methods should now be scaled up for clinical practice and public health programs to improve BP control in communities.

Pharmacists have been widely employed in team-based care for hypertension. 145 A recent meta-analysis of 6 randomized trials involving 2,573 participants demonstrated that pharmacist interventions resulted in better BP control than usual care [OR 1.53 (CI 1.15-2.04), P<0.01]. 146 Pharmacist interventions using home-based BP telemonitoring were superior to usual care, whereas pharmacist intervention without BP telemonitoring did not improve BP control. In addition, a pharmacist-led intervention in a community setting for non-Hispanic Black male patrons of barbershops with uncontrolled BP resulted in a mean SBP reduction of 21.6 mm Hg greater than usual care at 6 months. 147 An advantage of pharmacist-provided hypertension care is that the effects often persist beyond the initial intervention period.

Advances in health information technology, including electronic health records and high-speed communications, provide ideal opportunities for improving BP control in patients with hypertension. Telemedicine is a revolutionary patient management tool facilitating interactive communication between the patient and the health care team from remote sites. 148 Telemedicine combines various forms of information technology to deliver care, consultation, medical education, and specific health and clinical services, including monitoring. Telemonitoring, a specific application of telemedicine, refers to remote monitoring of various vital and nonvital parameters, including BP, that are automatically communicated directly to the health care team.

Until recently, evidence for the use of BP self-monitoring and telemonitoring to titrate antihypertensive medication by physicians was equivocal. However, telemonitoring and/or self-monitoring of BP in the TASMINH4 trial provided new evidence that physician drug titration using patient self-monitoring led to lower BP and that including telemonitoring led to lower BP more rapidly than self-monitoring alone. 149 These approaches were also cost-effective. 150

Several meta-analyses based on numerous RCTs reported to date provide moderate to high level evidence that home BP telemonitoring enhances hypertension management and improves BP control in hypertensive patients. 148 The most successful BP telemonitoring approach seems to be BP data exchange with a case manager (eg. nurse or pharmacist) combined with education on lifestyle, risk factors and appropriate dosing of antihypertensive medications. Proactive intervention driven by the health care professional, rather than passive intervention, seems to provide the best and most long-lasting effects. A recent position paper on the use of telemedicine in the management of hypertension concludes that current evidence supports the use of telemedicine and BP telemonitoring, particularly in patients with difficult to control hypertension or those with poor adherence to their antihypertensive regimen. 148

Conclusions

Hypertension is the world’s leading risk factor for CVD and mortality. Since publication of the 2017 ACC/AHA BP Guideline, several new findings have emerged which, taken together, can better inform the approach to the prevention, detection and management of hypertension. The major findings (January, 2018-March, 2021) and their relevance to the management of hypertension are summarized in Table 7 . This new information has the potential to increase hypertension awareness, treatment and control which are bedrock for the prevention of CVD morbidity and mortality in the future.

Summary of Major Findings (January, 2018-March, 2021) and Relevance to the Management of Hypertension

ABPM, ambulatory blood pressure monitoring; ACC, American College of Cardiology; AHA, American Heart Association; BP, blood pressure; HBPM, home blood pressure monitoring; MH, masked hypertension; TOD, target organ damage; WCH, white coat hypertension.

Supplementary Material

318083 online, sources of funding.

Dr. Carey is Principal Investigator and Project Director of an NIH Research Grant (R01-HL-128189) and Program Project Grant (P01-HL-074940), respectively. Dr. Wright is supported by a grants from the Ohio Department of Medicaid and Agency for Health Care Research & Quality (1U18HS027944-01). Dr. Taler is a staff physician at Mayo Clinic, Rochester, MN with no outside funding to disclose. Dr. Whelton was supported by a National Institute of General Medical Sciences, Centers of Biomedical Research Excellence award NIGMS P30-GM-109036.

Non-standard Abbreviations and Acronyms

Disclosures

Dr. Carey was Vice-Chair of the 2017

ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults Writing Committee, Chair of the AHA Scientific Statement on Resistant Hypertension Writing Committee and a Member of the 2019 AHA Scientific Statement on Measurement of Blood Pressure in Humans Writing Committee. . Dr. Wright was a member of the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults Writing Committee and the 2019 AHA Scientific Statement on Measurement of Blood Pressure in Humans. Dr. Taler was a member of the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults Writing Committee and a Member of the 2018 AHA Scientific Statement on Resistant Hypertension Writing Committee. Dr. Whelton was Chair of the SPRINT Steering Committee and Chair of the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults.

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Hypertension articles from across Nature Portfolio

Hypertension is high blood pressure. It is generally defined in adults as systolic blood pressure greater than or equal to 140mmHg and/or diastolic blood pressure greater than or equal to 90mmHg. Rarely associated with obvious symptoms, hypertension can result in heart disease, vascular disease, stroke and/or chronic kidney disease

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Health Equity Research Network on Prevention of Hypertension

The Health Equity Research Network (HERN) on the Prevention of Hypertension is part of the multi-pronged approach of the American Heart Association’s unprecedented pledge to aggressively address social determinants while working to support and improve the equitable health of all communities. High blood pressure is one of the leading risk factors of heart disease and stroke and is also a health equity issue. Significant racial and ethnic disparities in both prevalence of hypertension and its management have been well documented. Uncontrolled hypertension is particularly acute in communities of color. As such, this research initiative provides a mechanism to advance the science of prevention of hypertension with a focus on health equity.

  Health Equity Research Network on Prevention of Hypertension RFA (pdf)

AHA Awards $20 Million for Research to Ensure Health Equity in Preventing Hypertension

Teams from Beth Israel Deaconess Medical Center, Johns Hopkins University School of Nursing, NYU Grossman School of Medicine, the University of Alabama at Birmi ngham, and Wayne State University received American Heart Association research grants to study high blood pressure prevention in underrepresented populations.  The projects focus on hypertension prevention in underrepresented populations who historically have the highest prevalence of this mostly preventable but potentially deadly condition.

Progress Updates

Published papers highlights.

The RESTORE network overview and five individual study protocol papers were recently published in the American Journal of Hypertension: https://academic.oup.com/ajh/issue/36/5

Network Update

Dr. Gbenga Ogedegbe talks about his role in the Health Equity Research Network on Prevention of Hypertension

Presentations at AHA Hypertension Scientific Sessions 2022

RESTORE Health Equity Research Network participants describe the context and theoretical framework of the network and provide a brief overview of the five innovative, evidence-based projects the AHA has funded to improve health equity in Black communities.

RESTORE (AddREssing Social Determinants TO pRevent hypErtension) Network

RESTORE (AddREssing Social Determinants TO pRevent hypErtension) Network is the name of the overarching research program. It will be managed by a multidisciplinary team from NYU Grossman School of Medicine, led by Gbenga Ogedegbe, M.D., M.P. The coordinating center will oversee the establishment of and provide support and resources to the five research projects. The RESTORE Network will be testing multiple approaches to helping people overcome the barriers to health faced by many living in neighborhoods with poor access to health care, healthy foods and places to exercise.

• Groceries for Black Residents to Stop Hypertension (GOFRESH) at Beth Israel Deaconess Medical Center in Boston, led by Stephen P. Juraschek, M.D., M.P.H., will test the use of a virtual grocery list with weekly healthy food delivery to the homes of Black adults with high blood pressure in Boston neighborhoods. The groceries will be balanced as part of the healthy eating plan known as the DASH (Dietary Approaches to Stop Hypertension) diet, known to be high in important nutrients and low in sodium. A dietitian will help study participants order the groceries they prefer by computer, as well as providing them with tips and recipes on how to prepare foods in new ways. Over the course of the three-month clinical trial, the researchers will evaluate the impact of grocery delivery on blood pressure and cholesterol.
• Home Blood Pressure Telemonitoring Linked with Community Health Workers to Improve Blood Pressure (LINKED-BP)  at Johns Hopkins University School of Nursing in Baltimore – Led by Yvonne Commodore-Mensah, this team will implement its LINKED-BP Program to help people who receive care at community health centers. The program will provide some participants with a home blood pressure machine, connections to a community health worker and a mobile health app. Others will be given the blood pressure monitor only. Over the course of 12 months, researchers will evaluate whether people who receive these interventions were able to lower their blood pressure and will compare the outcomes of the higher intervention group to the one with only the home blood pressure monitor.
• Community-to-Clinic Implementation Program (CLIP)  at NYU Grossman School of Medicine - Led by Joseph Ravenell, M.D., this team will engage 30 barbershops in their study to screen Black men for high blood pressure, give them advice about a healthy lifestyle and link them to health care when needed. The team will expand their initiative, called  Community-to-Clinic Linkage Implementation Program (CLIP), in three phases to test various interventions. In the first phase, they will learn about concerns barbershops may have about CLIP and help barbershops put the plan into practice. In the second phase, they will evaluate whether giving the barbershops “expert help” for 12 months helps the shops adopt CLIP more quickly and if the expert help leads to lower blood pressure in customers. In the third phase, they will determine whether the shops still have CLIP in place six months after expert help ends. They will also put CLIP into place in barbershops without expert help and compare the effectiveness of the two different ways to implement the program.
• Linkage, Empowerment, and Access to Prevent Hypertension (LEAP-HTN) at Wayne State University in Detroit – Led by Phillip Levy, M.D., M.P.H., this team will deploy mobile health units to provide direct, personalized health care and coaching to people with high blood pressure living in Black neighborhoods of Detroit. Community health workers will help people in the study develop and follow a personalized, flexible health plan. Throughout the year, researchers will regularly compare hypertension and other health factors of people in the program to those of people in the community who also have high blood pressure but who didn’t take part in the personalized health plan. They anticipate people receiving care from the community health workers will have lowered or better controlled their blood pressure compared with those who were not.
• Equity in Prevention and Progression of Hypertension by Addressing barriers to Nutrition and Physical Activity (EPIPHANY) at the University of Alabama at Birmingham – Led by Andrea Cherrington, M.D., M.P.H., this team will work with 16 churches in rural Alabama to recruit Black adults with elevated but unmedicated high blood pressure to take part in one of two interventions. People from eight of the churches will receive group health education and personal tablets to access online cooking shows and exercise classes. People in the other eight churches will get support from a health coach over the telephone to help set and meet diet and physical activity goals. These participants will also receive the group health education and tablets to access online cooking shows and exercise classes and some of them will be encouraged to sign up as health coaches. The churches will also receive funds to help bring healthy foods and/or physical activity opportunities to their communities. 

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