Epidemiologic features and Management of Hypertension in Tunisia, the results from the NAtional TUnisian REgistry of HyperTensioN (NaTuRe HTN) about 25890 patients

Background Hypertension is the leading cause of morbi-moratlity in low, middle as well as high incomes countries. Tunisia is a developing country with a high cardiovascular prole and the prevalence of hypertension has widely increased during the last decades. Thus, we conducted this national survey on hypertension to analyze the prole of the Tunisian hypertensive patient and to assess the level of blood pressure control. Nature HTN is an observational multicentric survey, including hypertensive individuals and consulting their doctors during the period of the study. The primary endpoint of our study was uncontrolled hypertension dened by a systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90mmHg. Our objective is to assess the predictors of uncontrolled hypertension in our population. high educational level (OR=0.9, 95% CI [0.84-0.97], absence of history of coronary disease (OR=0.86, 95% CI [0.8-0.93]), salt restriction (OR=0.48, 95% CI [0.45-0.51]), drug compliance (OR=0.57, 95% CI[0.52-0.61]) and regular physical activity (OR=0.77, 95% CI[0.71-0.84]) are strong predictors of blood pressure control.


Abstract Background
Hypertension is the leading cause of morbi-moratlity in low, middle as well as high incomes countries. Tunisia is a developing country with a high cardiovascular pro le and the prevalence of hypertension has widely increased during the last decades. Thus, we conducted this national survey on hypertension to analyze the pro le of the Tunisian hypertensive patient and to assess the level of blood pressure control.

Methods
Nature HTN is an observational multicentric survey, including hypertensive individuals and consulting their doctors during the period of the study. The primary endpoint of our study was uncontrolled hypertension de ned by a systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90mmHg. Our objective is to assess the predictors of uncontrolled hypertension in our population.

Results
Three hundred twenty one investigators from all the Tunisian governorates participated in the study. We enrolled 25890 patients with a female predominance (Sex ratio 1.21) and an average age 64.4±12.2 year-old. Most of individuals were treated in the public sector (74%), 39.4% of patients were diabetic, 25

Conclusion
Nature HTN showed a remarkable improvement of blood pressure control amongst Tunisian people. The control remains low in patients with high cardiovascular pro le and those treated in the public sector. A national health program based on therapeutic education, regular control and continuous giving much support to the public institutions is needed to decrease the hypertension burden affection rate in our population.

Background
Hypertension is the most common chronic disease in the world with a prevalence ranging between 30 and 50%, and it is considered to be the leading cause of morbi-mortality in adults especially in low and middle incomed countries [1][2][3][4][5]. The prevalence is higher in the elderly and exceeds 60% in people aged > 60 years [3]. Given the widespread of sedentary lifestyles and obesity, the prevalence of hypertension worldwide will continue to rise. It is estimated that the number of hypertensive people will increase by 15-20% by 2025, reaching close to 1.5 billion [2]. Several recent epidemiological studies demonstrated that high blood pressure is under diagnosed in the 5 continents of the world and despite the development of the therapeutic arsenal, the control of hypertension does not seem to improve in most countries [4,[6][7][8][9][10].
In Tunisia, a middle income developing country, the latest epidemiological data related to hypertension dates back to 2012, from the national survey "TAHINA Study" [11]. The lifestyle of Tunisian people has widely changed in last years with an increase of sedentarity, overweight and obesity, diabetes and dyslipidemia… Tunisia is considered as a high cardiovascular risk country [12] and the world health organization as well as other international organizations estimate that the Tunisian epidemiologic situation will worsen in next years [13]. The main reason why we envisioned the need for a national multicentric survey to analyze the epidemiologic pro le of hypertension in Tunisia and to assess the level of blood pressure control as well as the predictor of uncontrolled hypertension.

Patients And Methods
Nature HTN registry is an observational multi-centric national study, conducted in all the governorates of Tunisia, in both public and private health sectors. Patients were included between 15 April 2019 and 15 May 2019 (Ramadan in between).
Different investigators ensured the enrollment and the clinical examination: Cardiologists, General doctors as well others specialists as Nephrologists, Endocrinologists and Internists. We included all patients with known or new diagnosed hypertension, who consulted their doctors during the enrollment period.

Inclusion Criteria
We included during the o ce visits, patients with a history of or newly diagnosed elevated blood pressure and older than 18 year-old, after signing a consent form.
Except when hypertension is severe (e.g. grade 3 and especially in high-risk patients), the diagnosis of new hypertension was con rmed according to the ESC/ESH guidelines as either Out-of-o ce Blood Pressure (BP) measurement above the recommended thresholds or repeated o ce BP measurements on more than one visit above 140 mmHg for the systolic pressure and /or 90 mmHgfor the diastolic pressure [14].

Exclusion Criteria
We excluded from the study, patients undergoing hemodialysis, pregnant women, those classi ed as white coat hypertension patients and those who refused to sign the consent form.

Clinical evaluation and data collection
During the o ce visit, the physician had to complete the case report form of the registry after patient's interrogation and examination.
Information's on socio-demographic characteristics including age, gender, education level, health insurance, smoking, diabetes, pulmonary diseases, hypothyroidism, moderate renal failure history (de ned by an MDRD creatinine clearance < 60ml / min [15]), coronary disease as well as history of stroke were collected.
The interview-included questions related to drug compliance and salt intake as well as sport practice. The physical activity was considered as regular when it was performed at least 30 minutes three times a week [14].
On physical exam, we measured weight and height to assess body mass index (BMI = weight/height 2 . Obesity is operationally de ned as a BMI exceeding 30 kg/m 2 and is subclassi ed into moderate (BMI:30-34.9), morbid (BMI:35-39.9) and severe (BMI ≥ 40) [16]. Blood pressure measurements were conducted using a standardized auscultatory or oscillometric sphygmomanometer after at least 15 min of rest. Two separate readings were taken at least three minutes apart and we considered the average of the two measurements. In patients with asymmetric blood pressure between the two arms, we considered the higher pressure.
We checked on electrocardiogram whether the patient had a sinus rhythm or atrial brillation and we searched for left ventricle hypertrophy (LVH) based on the de nition recommended by the ESC/ESH guidelines (Sokolow-Lyon index > 35 mm, or R in aVL >_11 mm) [14]. We searched for LVH also on echocardiographic ndings (if the patient underwent echocardiography during the last year).
We noted also the last biology tests, performed during the last six months before the o ce visit, especially creatinine, glycaemia, cholesterol and kaliemia as well as microalbuminuria ( if performed during the last year).
To assess control blood pressure, we evaluated only patients with diagnosed hypertension for more than 6 months. The primary endpoint in our study was the rate of hypertension control.
Uncontrolled hypertension was de ned according to the ESC/ESH guidelines as an average systolic blood pressure(SBP) above 140mmHg and/or an average diastolic blood pressure (DBP) above 90mmHg [14].
A validation of the study protocol and the consent form by a national ethic committee was also obtained.
The data collected, were managed by the Clinical Suite platform (Dacima Software), which complies with international standards including US Food and Drug Administration 21 Code of Federal Regulations Part 11, US Health Insurance Portability and Accountability Act, International Conference on Harmonisation, and Medical Dictionary for Regulatory Activities. The Clinical Suite platform allowed us to track the data entered and to check for inconsistencies and missing data. A steering committee was set up to monitor patient inclusions, verify data sources, perform the audit trail, and prepare the statistical analysis plan for the study.
We con rm that all methods were carried out in accordance with relevant guidelines and regulations. All experimental protocols were approved by the ethic committee of the Hospital of the Internal Security Forces. An informed written consent was obtained from all subjects. In case of illiterate participants informed consent was obtained from legal guardians.

Statistical analysis
All statistical analyses were achieved using the SPSS 23.0 (SPSS, Chicago, IL, USA) statistical package. Continuous variables were presented as means value ± standard deviation in case of Gaussian distribution and as medians as well as extremes values in case of non-Gaussian distribution.
Among patients with old hypertension more than 6 months, we distinguished two groups according to the hypertension control (controlled group versus uncontrolled group). The comparison between the two groups was achieved by Student's ttest and Chi2 test for continuous variables and categorical variables, respectively. Univariate logistic regression analyses were used to determine crude odds ratio with the 95% approximate con dence intervals as estimators of the non-control of hypertension for various characteristics of the study population. To assess the predictors of hypertension non control, we performed a multivariate logistic regression model. The signi cance threshold was set at p < 0.05.

Results
The Nature HTN registry concerned 25890 hypertensive patients, enrolled by 321 investigators from all the Tunisian governorates. The case report form was completed by Cardiologists in 71% of patients, general practitioner in 25% and others specialists in 4%. The patients were managed in public as well as private sector but the majority of patients were followed in public centers (78%). The hypertension was newly diagnosed in 2286 patients (8.8%) and in the medical history/record of more than six months in 23601 persons.
The majority of patient (16565, 64%) were included during Ramadan, especially for private sector.
The epidemiologic and clinic characteristics of the overall population are summarized in Table 1. On univariate analysis, patients with uncontrolled hypertension were signi cantly older, more frequently diabetic, obese and smokers. They were followed in the public sector, with more frequent history of strokes, and moderate renal failure antecedents. These patients had also higher pulse rate (74.9 ± 11.4 bpm versus 72.5 ± 10.5 bpm, p = < 0.001). They practiced less frequently sport (11.5% versus 18.1%, p < 0.001) and are less compliant to the drug intake and the salt restriction.
Control of BP was better during the holly month (Ramadan), among 15239 hypertensive patients included during this month, with HTN history > 6 months, 53.3% individuals were in target.
Contrariwise, patients with controlled hypertension had more frequently a history of coronary diseases than others (19.9% versus 18.8%, p = 0.033), underwent more frequently electrocardiogram and echocardiography control and showed less frequently left ventricle hypertrophy (Table 2). Based on multivariate analysis, predictors of uncontrolled hypertension were of male gender, old age > 65 yo, diabetic, obese, smokers, in public sector management, HR more than 80 bpm. Contrariwise, predictors of controlled hypertension were of high educational level (secondary/university), with a history of coronary disease, salt restriction, drug compliance and regular physic activity (Table 3 and Fig. 1).

Discussion
Hypertension is the most prevalent cardiovascular factors worldwide and is the main cause of death even in developed country [17]. Recently a large meta-analysis of 2939 sudden cardiac deaths (SCD) among 418,235 participants from 18 studies, showed that hypertension is associated with a twofold increase in risk of SCD and a 28% increase of SCD per 20 mmHg increment in SBP [18]. Moreover, in a pooled dataset from 44 low-income and middle-income countries including 1100507 participants, the authors showed that only 10.3% of hypertensive patients achieved BP control [9]. All these indicators demonstrate that hypertension is a public health problem in developed as well as developing countries. Tunisia, is a mild incomes country, and during the last decade, the Tunisian lifestyle, eating habits and the population ageing have widely changed; there has been an increase in cardiovascular risk factor [19]. Recently a national cross sectional Tunisian study "ATERA", including 11 955 individuals showed that the prevalence of high blood pressure has increased to 50%, that of diabetes to 18% and that of obesity to 31% [20]. Face to these dramatic epidemiologic indicators, the Tunisian Society of Cardiology and Cardiovascular surgery, aimed to evaluate the cardiovascular pro le of hypertensive patients and to assess the BP control, through a national ash study. In our knowledge, Nature HTN is the largest national survey of Hypertension in Africa. The most important ndings of this registry is that the pro le risk of the Tunisian has changed remarkably. In Nature HTN among hypertensive patients, we found that the prevalence of illiterate people has decreased from 43-21.3%. Surprisingly, we found that the prevalence of diabetes among hypertensive people has deacreased from 62-39.4%, that of tobacco from 22-14% and that of obesity from 46-25% [11]. All these ndings demonstrate that nowadays, the diagnosis of hypertension was made early before the development of diabetes and other comorbidities. That's why the rate of diabetic among hypertensive patients has decreased. This nding goes along with the improvement of the educational level between the two studies, certainly the Tunisian citizen 's awareness of blood pressure risks, and management methods has evidently increased. This rate is close to the rate achieved in many developed countries. Control of hypertension remains elusive nationally, despite widespread availability of effective therapies.
In fact, control hypertension remains a health problem in not only low and middle incomes countries but also even in high incomes countries. Ikeda et al, in a comparative analysis of national surveys in 20 countries, showed that hypertension was treated in 13.8-80.5% of hypertensive patients in the different countries but was controlled only in 4.4 % to 59.1% [10].
Recently, Pan et al reported a control of 60% of hypertensive patients in Taiwan, but the prevalence of diabetes, obesity and smoking in this cohort were lower compared to our population [21].
In California, the implementation of a large-scale hypertension program has been associated with a signi cant increase in hypertension control compared to the others cities of US. In our population, the BP control has improved, the reimbursement of Stage II and III hypertension costs as well as the availability of generic molecules, the improvement of the education level of the Tunisian population has certainly contributed to this achievement. However, management of patients in public sector was found as an independent predictor of uncontrolled hypertension. Certainly, this could be explained in part by the discrepancy of drug availability between the two sectors, the quality of health insurance and the lack of one single pill in public sector. However, we it is worth considering that we found in our cohort that patients treated in public sector seem to be at higher cardiovascular risk with higher prevalence obesity, diabetes, smoking with a less frequently physical activity. All these factors were identi ed as predictors of uncontrolled hypertension in our population and were behind the bad control of BP in public sector. Moreover, patients treated in the private sector ,underwent more frequently out o ce measurement, they had lower heart rate, better follow up with more frequent lab test. We noted also that ARB Class was more frequently prescribed in private sector and this class is associated with better tolerance and persistence. In public sector, the majority of patients take their drugs from the hospital. ARB class was not available in public sector. All these ndings should be considered by the health ministry to improve the conditions of management of hypertensive patients in public sector where patients with the highest cardiovascular pro le were treated.
The reimbursement of stage I hypertension costs by the national security fund is another point to discuss and which is missing both, in private and public sector. There is an urgent need for a comprehensive integrated population-based intervention program to improve the growing problem of hypertension in Tunisia.
Heart rate was another strong predictor of uncontrolled BP in our population and this is could be related to the big prevalence of overweight and obesity as well as the low physical activity practice. One patient out of ve has a heart rate > 80bpm in our model. Recently, the ESC/ESH guidelines classi ed this clinical nding among the factors in uencing cardiovascular risk [14,24]. The Nice guidelines recommended to downgrade beta-blockers use and to limit their use to the speci c settings [25], but we thought that sympathic activation is well involved in the physiopathology of hypertension in Tunisian people, as it was demonstrated by the high Heart rate in our population [26]. Therapeutic education should be highly considered and practicing sports to reduce BP level highly recommended. In developed countries, 60% of the population practice sport regularly [27], in our study only 14% performed a physical activity. Recently, Sata rosa et al showed that active life style improves heart rate variability as well as reduces oxidative stress in hypertensive people and it improves BP control [28]. On the other hand, Beta blockers should not be dismissed, and patients with high HR, de nitely need this therapeutic class.
Patients with a history of coronary disease were more in target in our model and ischemic cardiomyoapthy was even identi ed as a predictor of controlled blood pressure. Many previous studies have con rmed these ndings [6,7,10,29], in fact patients with coronary disease are more compliant to their drugs and generally receive at least two class (beta blockers and ACE or ARB), moreover they consult their doctors more frequently.

Limits Of The Study
The main limit of our registry that it included only con rmed patients and didn't aim to assess the prevalence of hypertension, the rate of undiagnosed and non-treated hypertensive patients. If all these groups were considered, the control rate would be lower.
On the other hand, the de nition of hypertension control was based on o ce measurements, we did not complete with a systematic out o ce measurements to check the white blouse high blood pressure effect, therefore the rate of uncontrolled patients could be over-estimated in this registry.
Finally, this cross sectional study did not evaluate the clinical follow up and the impact of uncontrolled blood pressure on cardiovascular events.

Conclusions
Nature HTN is the largest national survey of hypertension in Tunisia, it would contribute to analyze the burden of hypertension in a developing country, and highlight the important gaps in the treatment of hypertensive individuals.
Certainly, it may help to guide the implementation of future interventions and to write national guidelines. The most important nding of this registry is that the control of hypertension has remarkably improved over the last years, although a high cardiovascular risk of our population. Therapeutic education along with substantial support and interest to the public sector are important preventive measure that can contribute to the public health in Tunisia.

Declarations
Ethics approval and consent to participate An ethical approval letter has been obtained from the ethic committee of the Hospital of the Internal Security Forces. A written consent was obtained from all subjects. In case of illiterate participants written consent was obtained from legal guardians.

Consent for publication
Not applicable Availability of data and materials Data cannot be shared publicly because of privacy concern. Indeed, data might reveal the identity and the location of participants included into the study. Data are available from the Tunisian Society of Cardiology and Cardiovascular Surgery Ethics Committee (contact via Résidence les pergolas, Rue du Lac Huron Appartement 201, Berges du Lac -Tunisie, Email: secretaire.stcccv@gmail.com; Tel: (+216) 71 965 432) for researchers who meet the criteria for access to con dential data. there were no administrative permissions required to access the raw data from.

Competing interests
Authors declare that they have no con ict of interest.

Funding
Not applicable

Authors' contributions
Leila Abid was a principal investigator.Rania Hammami was a major contributor in writing the manuscript. Yosra Mejdoub performed statistical analyzes. The other authors were investigators, they included their patients. All authors read and approved the nal manuscript.
Imen gtif is a co-author and an investigator. Figure 1 Forest Plot graph: Predictors of Blood pressure control according to the Multivariate regression analysis BP: Blood Pressure, bpm: beat per minute, CI: con dence Interval, HR: Heart rate, OR: odd ratio, Yo: year old