Prevalence, awareness, treatment, and control of hypertension in the PERSIAN cohort study: JNC7 versus ACC/AHA guidelines

In this cross-sectional population-based study, we used the baseline data of the Prospective Epidemiologic Research Studies in IrAN (PERSIAN) cohort study collected in Iran from 2014 to 2020. The main outcomes were the prevalence of hypertension and proportion of awareness, treatment, and control based on the 2017 ACC/AHA guideline compared to the seventh report of the Joint National Committee (JNC7). Of the total of 163770 participants, aged 35 to 70 years, 55.2% were female. The sex-age standardized prevalence of hypertension was 22.3% (95% CI: 20.6-24.1) based on the JNC7 guideline and 36.5% (31.1-41.8) based on the ACC/AHA guideline. A total of 24312 participants [14.1% [10.1, 18.1)] were newly diagnosed based on the ACC/AHA guideline. Compared to adults diagnosed with hypertension based on the JNC7 guideline, the newly diagnosed participants were mainly young literate males who had low levels of risk factors and were free from conventional comorbidities of hypertension. About 30.7% (25.9, 35.4) of them (4.3% of the entire population) were eligible for pharmacologic intervention based on the ACC/AHA guideline. Implementation of the new guideline may impose additional burden on health systems. However, early detection and management of elevated blood pressure may reduce the ultimate burden of hypertension in Iran.


Introduction
In 2017, the American College of Cardiology/American Heart Association (ACC/AHA) guideline was released 1 , in which lower thresholds (>=130/80 mmHg) were recommended for hypertension, and the upper end of prehypertension based on the seventh report of the Joint National Committee (JNC7) 2,3 was reclassified as stage 1 hypertension. The rationale for this shift is the evidence showing that adults with blood pressure in this range have an approximately 2-fold increase in risk of cardiovascular diseases (CVDs) compared to adults with normal blood pressure. 4,5 Additionally, recent randomized clinical trials have demonstrated benefits from a systolic blood pressure (SBP) lower than 130 mm Hg 6,7 including the Systolic Blood Pressure Intervention Trial (SPRINT) which demonstrated substantial reduction in CVD events by applying an intensive systolic blood pressure target <120 mmHg. 8 In a very recent study, Whelton et al reported that the stepwise rise in incident atherosclerotic CVDs and presence of coronary artery calcium begins at SBP levels as low as 90 mmHg. 9 However, the implications of the new hypertension definitions are under debate. Using lower thresholds for definition of hypertension will lead to increase in estimated prevalence, which will impose additional burden on health systems especially in low-middle income countries with limited resources. [10][11][12][13] On the other hand, early diagnosis and treatment of high blood pressure among adults previously classified in the category of "pre-hypertension" may lead to reduced all-cause and CVD-specific mortality and morbidity. 5,13 Primordial prevention seems to be a necessity for maintaining optimal blood pressure levels even in adults free from traditional risk factors of CVD. 9 5 Studies demonstrate that all-cause mortality and cardiovascular deaths attributable to high blood pressure doubled in Iran since 1990 and hypertension is the most important risk factor responsible for mortality in both sexes. 14,15 It is of utmost importance to explore the impacts of stricter definitions for high blood pressure prevalence, treatment, and control to reduce the burden of CVD in a country with a high prevalence of hypertension as a middle-income nation.
The main objective of the current study was to determine the impact of the two guidelines on estimated prevalence, awareness, treatment, and control of hypertension among a very large group of Iranians residing in various regions across the country.  Figure 1). The prevalence of hypertension based on the JNC7 guideline was significantly higher among females compared to males. In contrast, there was no difference in hypertension prevalence between sexes based on the ACC/AHA guideline. The prevalence of hypertension was greater with age regardless of guideline ( Figure 2 42.9%), but the proportion of literacy was not different between the two groups. Awareness was higher among females and increased by age based on the ACC/AHA guideline ( Figure 2).

Results
The proportion of treatment among hypertensive adults was 82.2% (77.6-86.9) and 50.4%  Figure 1). In short, among the entire study population, 14.1% were newly diagnosed with hypertension based on the ACC/AHA guideline, while only 30.7% of these newly diagnosed adults (4.3% of the entire population) were eligible for pharmacologic treatment.

Discussion
In the current study, representing a large number of the Iranian population, a total of 6.5 million and 10.7 million Iranians aged 35 to 70 years, have hypertension based on the JNC7 and the ACC/AHA guidelines, respectively. Although there was some heterogeneity in prevalence across study centers, the application of the ACC/AHA guideline uniformly led to increase in relative prevalence (by 63.7%) and decrease in relative awareness (37.3%), treatment (38.7%), control among hypertensive adults (63.4%), and control among treated adults (39.5%). Yet, the increase in prevalence observed in our study was still lower than previous studies in Iran, which reported a more than a 2-fold higher prevalence based on the ACC/AHA guideline. [16][17][18] Less than 2-fold increases were also observed in other countries. 10,11,19,20 The results of our study showed that a total of 24 312 adults who were previously classified in the category of "pre-hypertension", were shifted to stage 1 of hypertension based on the ACC/AHA 2017 guideline. These adults were mainly young and educated males, and many of them free from other metabolic risk factors and comorbidities of high blood pressure with a low 10-year risk of CVD events. These findings may mean that apparently healthy young lowrisk male adults may be prone to developing high blood pressure later in life and they shall be detected and managed at early stages, particularly considering the fact that the risk of CVD mortality in males is higher than females, specifically in younger age groups. 5,21 Implementation of the guideline necessitates that the public be informed and health care professionals use the updated guideline in practice. The result will be a higher number of adults diagnosed with hypertension, who should refer to health care professionals and be managed. There will thus be an apparent additional burden on health care systems. It is worth noting, however, that not all newly-diagnosed adults will require pharmacological treatment. Based on the new guideline, less than one third of the newly diagnosed adults, and mostly elderly groups, will require pharmacological treatment. Therefore, the guidance will not increase medication utilization among the majority, but will hopefully improve awareness and subsequent lifestyle modification before developing very high levels of blood pressure and its accompanying comorbidities later in their lives. 13  Our study has certain limitations. Despite the large scale of the study and the unique and standard protocol used in its design and implementation, there were variations in outcomes between centers. Therefore, we used study centers as the primary sampling units in our survey data analysis. The cross-sectional design of the study is another limitation that makes it impossible to explore and prove causal relationships. The third limitation is the exclusion of adults younger than 35 years from the study (based on the predetermined protocol of PERSIAN).

Conclusions
Overall, our results showed that implementation of the 2017 ACC/AHA guideline will lead to shifting a group of mainly young male adults to the category of stage 1 of hypertension. Future longitudinal studies are mandatory to explore whether the implementation of this strict guideline is cost-beneficial in various settings, especially in low and middle income countries with limited resources. The results of this study demonstrated the "clustering" of metabolic risk factors, which necessitates an integrated approach towards primordial prevention of these risk factors.

Study design
The current study used data from the Prospective Epidemiologic Research Studies in IrAN climates. The exclusion criteria were unwillingness to participate in the study, living in the designated area for less than 9 months, and physical and psychosocial disability impeding the enrollment process.
In the first step, trained personnel visited households to invite eligible individuals (based on inclusion criteria) to participate in the study. If individuals agreed to participate, they were requested to refer to their local cohort center in overnight fasting state and to bring the medications they use. Upon arrival, written informed consent form was obtained from all participants. They underwent biospecimen collection (blood, urine, hairs, and nails) as well as anthropometric measurements, following protocols established by the US National Institutes of Health. 39 A structured questionnaire including 482 items was filled out during a face-to-face interview. Demographic characteristics, socioeconomic status, lifestyle, past medical history and family history, and medication history were queried. PERSIAN was approved by the ethics committees of the Digestive Disease Research Institute in Tehran University of Medical Sciences and Health Services, and the Medical Sciences Universities supervising each cohort in local study centers. All methods were carried out in accordance with relevant guidelines and regulations. Participants in PERSIAN will be followed for up to 15 years.

Definitions of outcomes
The main outcomes in this study were prevalence, awareness, treatment, and control of hypertension, and eligibility for treatment based on both JNC7 2,3 and the 2017 ACC/AHA guidelines. 1 Treatment was defined as self-reported intake or the antihypertensive medications that the participant brought with himself/herself to the study center. Awareness was defined as self-reported history of being diagnosed with hypertension by a physician or a health care professional. Trained personnel measured blood pressure in sitting position after 10 minutes of rest, twice from the right arm and twice from the left arm, with one-minute interval between each of the two consecutive measurements. The average of the second measurements from right and left arms were calculated and considered as the level of blood pressure. Multiple cuff sizes were available for use to best fit the participant's arm.

Definitions of determinants
Demographic characteristics included sex, age, area of residence (rural, urban), and marital status (married versus non-married). Socio-economic status was defined based on education and wealth index. Education was defined in 5 levels: no schooling (<1 year of primary school), primary school (1-5 years), middle school (6-8 years), high school (9-12 years), and university (>12 years). Wealth index was calculated using multiple correspondence analysis (MCA) on household assets and divided into 5 quintiles. For physical activity, metabolic equivalents of tasks (METs) were calculated and divided into tertiles. Body mass index (BMI) was calculated and divided into four groups: underweight (<18.5 kg/m 2 ), normal (≥18.5 and <25 kg/m 2 ), overweight (≥25 and <30 kg/m 2 ), and obese (≥30 kg/m 2 ). A high waist to hip ratio (WHR) was defined as a ratio ≥ 0.9 in males or ≥0.85 in females. Diabetes was defined as self-reported usage of relevant medications or fasting blood sugar (FBS) ≥ 126 mg/dL. Dyslipidemia was defined as low density cholesterol (mg/dL) ≥ 160 and/or total cholesterol (mg/dl) ≥240 and/or high density cholesterol (mg/dL) < 40 and/or reporting a history of using lipid lowering medications. Chronic kidney disease (CKD) was defined as glomerular filtration rate (GFR) <60 ml/min. The 10-year risk of atherosclerosis CVD (ASCVD) based on the ACC/AHA guideline was calculated for all participants. 40

Statistical Analyses
We calculated the sex and age standardized prevalence of hypertension, the proportion of awareness, treatment, and control among hypertensive patients, the proportion of control among treated patients, and the proportion of untreated adults who were eligible for pharmacologic intervention based on both guidelines. Given the cluster sampling, we used a complex survey design to obtain summary measures. We used sampling weights defined as the inverse probability of being selected in the survey based on data of the national census in 2016.
For all estimates, 95% confidence intervals were reported. Data were analyzed using Stata Universities supervising each cohort in local study centers.

Data Availability
The data underlying this article will be shared on reasonable request to the corresponding author.