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

In this cross-sectional population-based study, we used the baseline data of the Prospective Epidemiologic Research Studies in IrAN 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 163,770 participants, aged 35–70 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 24,312 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.

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 twofold 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. 9 reported that the stepwise rise in incident atherosclerotic CVDs and presence of coronary artery calcium begins at SBP levels as low as 90 mmHg. 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 .
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 . JNC7 is still the widely used guideline for definition and treatment of hypertension in Iran, specifically among general physicians in remote areas. However, recent guidelines are gradually becoming popular. 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 middleincome nation. There is a slowly increasing trend towards using ACC/AHA guideline in Iran during the past couple of years. Therefore, exploring the potential impact of this guideline on definition, treatment, and control of hypertension in Iran is essential.
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.  (Fig. 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 (Fig. 2).
The proportion of awareness among hypertensive adults was 77.5% (73.3, 81.8) based on the JNC7 and 48.6% (41.9, 55.4) based on the ACC/AHA guideline. Among the reclassified participants, awareness was just 2.9% (1.5, 4.3). The reclassified participants aware of their elevated blood pressure compared to participants aware of their traditionally defined hypertension were mostly male (46.8 vs. 36.2%) and were less than 55 years old (64.9 vs. 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 (Fig. 2).
The proportion of treatment among hypertensive adults was 82.2% (77.6, 86.9) and 50.4% (43.3, 57.5) based on the JNC7 and the ACC/AHA guidelines respectively. None of the re-classified participants were treated ( Fig. 1). Treatment also increased by age and was higher in females based on both guidelines (Fig. 2).
The proportion of control among hypertensive adults was 63.7% (55.7, 71.7) and 23.3% (14.6, 32.0) based on the JNC7 and the ACC/AHA guidelines respectively. Control among hypertensive adults was higher in females.  (Fig. 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 35-70 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 twofold higher prevalence based on the ACC/AHA guideline [16][17][18] . Less than twofold increases were also observed in other countries 10,11,19,20 . www.nature.com/scientificreports/ www.nature.com/scientificreports/ 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 low-risk 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 .
A similar study in Italy showed that the new blood pressure classification moved 37% of individuals from "pre-hypertension" to "stage 1" and 41% from "stage 1" to "stage 2" hypertension. These results were quite similar to the results of the current study and show that redistribution of hypertensive patients according to the ACC/ AHA guideline may help to better identify uncontrolled hypertensive patients with high CVD risk profile 22 .
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 . The Heart Outcomes Prevention Evaluation (HOPE)-3 trial demonstrated that treatment of adults with intermediate CVD risk has no benefit 23 . Meanwhile, there is recent evidence on cost-effectiveness of a low-cost community-based plan focused on non-pharmacologic but including pharmacologic intervention in three low-income countries (Bangladesh, India, and Sri Lanka) 24 . These results highlight the importance of an integrated non-pharmacological intervention among low and intermediate-risk adults, as recommended in the 2017 ACC/AHA guideline, specifically feasible in low and middle-income countries. Reclassification of adults to higher stages of hypertension compared to previous guidelines is predominantly aimed at improving non-pharmacological interventions and life-style changes. This is the main reason for abolishment of the definition of "pre-hypertension" in recent US guidelines.
The new definition by ACC/AHA was derived from observational studies and clinical trials, focused specifically on results of Systolic Blood Pressure Intervention Trial (SPRINT) 8,25 . There are, however, a number of other studies and trials that don't support the new criteria and conclude that there is no additional benefit in implementing stricter definitions for hypertension 26,27 . Additionally, although not all newly-labeled hypertensive adults will require pharmacological treatment, there will be an increase in clinical encounters imposing burden of health system infrastructure. According to the AHA/ACC guideline, antihypertensive pharmacologic treatment is initiated for hypertensives with a blood pressure equal or higher than 140/90 mmHg, unless they are high risk 28 . This approach is similar to the ESC/ESH guidelines where for the overwhelming majority of hypertensives, treatment is initiated at this threshold and some consideration for pharmacological treatment can be given to adults with blood pressure 135-139/85-89 mmHg if they report CVD [29][30][31] . On the other hand, the American College of Physicians and the American Academy of Family Physician guideline was developed for adults 60 years and older and recommended pharmacological treatment to be initiated when SBP was 150 mmHg or higher, unless there was a prior history of stroke or transient ischemic attack, in which case pharmacologic treatment is initiated for blood pressures equal or higher than 140/90 mmHg 32,33 . In actuality, there are more similarities between the guidelines than differences 34 with the primary difference focused on the definition of stage 1 hypertension. www.nature.com/scientificreports/ The debate will remain unresolved until longitudinal large-scale studies are conducted on cost-effectiveness and adverse events of different approaches and guidelines [35][36][37] . Ultimately, it is worth mentioning that the apparent decrease in awareness, treatment, and control based on the ACC/AHA guideline is due to the fact that neither physicians and health care professionals are aware and use the new guideline in practice, nor the public are informed of the new criteria. Comparing awareness, treatment, and control between various guidelines will only be possible upon their implementation at large scale and for long time periods.
Educational campaigns provide excellent opportunities for improving the awareness of the public and the healthcare workers. World Hypertension Day, promoted by the International Society of Hypertension 38 , and the World Kidney Day 39 are two exemplar educational campaigns that share this specific goal by providing free blood pressure measurements. In the meantime, using smart phones or tablets can be an excellent option for improving awareness in the general public during the campaigns 40 .
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 next limitation is the exclusion of adults younger than 35 years from the study (based on the predetermined protocol of PERSIAN). The fourth limitation is that part of the data in this study was collected before the release of ACC/AHA guideline in 2017. Hereby, we actually aimed to explore what would be the impact if this guideline was applied. And the last limitation of this study is that the mean of first and second blood pressure measurement was used based on JNC7 instead of recording the highest based on the ACC/AHA guideline.

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.

Methods
Study design. The current study used data from the Prospective Epidemiologic Research Studies in IrAN (PERSIAN) cohort with a population-based cross-sectional design in the baseline recruitment phase. Detailed methods of PERSIAN are published elsewhere 41,42 In short, a total of 163,770 participants aged 35-70 years were recruited in 18 cohort centers located in 16 provinces in Iran between 2014 and 2020. Participants were recruited through cluster random sampling. The sample was selected to include all ethnic groups in Iran residing in regions with various 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. Data collected during the entire 6-year period has been aggregated in the current analysis.
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 signed by 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 43 . 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.
Protocols for blood pressure measurement were developed and validated in the pilot phase of the study. Personnel were meticulously trained by the core team of the PERSIAN to use Riester Exacta 1350 sphygmomanometers across all study centers. Sphygmomanometers were calibrated annually. Trained personnel measured blood pressure in sitting position after 10 min of rest, twice from the right arm and twice from the left arm, with one-minute interval between each of the two consecutive measurements. Personnel were specifically trained to round the measured blood pressure to the nearest 2 mmHg. 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. Trained supervisors at study centers monitored the process of blood pressure measurement and controlled the quality of measurement and data entry. Supervisors used a checklist for monitoring and evaluation of the blood pressure measurement conducted by each of the personnel. Personnel were retrained in case supervisors observed mistakes. www.nature.com/scientificreports/ 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 44 .
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 software (version 14.

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