Circadian blood pressure profile and comparison with clinic blood pressure in patients with essential hypertension on treatment ; experience from a Teaching Hospital in Sri Lanka

Background and Objectives Ambulatory blood pressure monitoring (ABPM) is more reflective of an individual’s blood pressure (BP) profile and its control, eliminating several confounding and contributory factors. This study looked at the circadian pattern of BP variation with respect to nocturnal BP fluctuations and compared clinic BP measurements with ambulatory readings in patients on treatment for essential hypertension Methods A prospective study was conducted at Teaching Hospital, Kandy from August to October 2015. The study participants were 100 patients, above 18 years of age, with stage I to III essential hypertension with normal renal functions and having no history of coronary or cerebro-vascular events. All patients underwent electrocardiography, 2D echocardiography, manual BP measurement and 24-hour ambulatory blood pressure monitoring. Results There was a female preponderance 72(72%) and the mean age was 61 ± 9 years. One third had uncontrolled BP, according to clinic BP readings, whereas 60% had uncontrolled BP according to ambulatory blood pressure monitoring. The agreement between the office BP and ABPM in diagnosing controlled or uncontrolled BP was low (58%, Kappa = 0.23). A significant statistical difference (p<0.001) was observed between day and night time measurements, irrespective of BP control. In the sample, 70% had abnormal dipping patterns including non-dipping (45%), reverse dipping (25%) and extreme dipping (5%). Conclusions and Recommendations ABPM is more reflective of an individual’s naïve BP pattern. It captures the different types of diurnal variation of BP thus guiding the physician to treat the patient optimally. Moreover, its noninvasive and portable nature allows it to be used with ease. It is likely that ABPM will gather widespread recognition and acceptance as a more reliable diagnostic and prognostic tool in the future Corresponding Author: HGWAPL Bandara, E-mail: <lakshmanbandara@gmail.com > http://orcid.org/0000-0002-8802-2014 Received: July 2017, accepted revised version October 2017, Published: January 2018 Competing Interests: Authors have declared that no competing interests exist This is an open-access article distributed under a Creative Commons Attribution-Share Alike 4.0 International License (CC BY-SA 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are attributed and materials are shared under the same license. October 7, December20 , Journal of the Postgraduate Institute of Medicine 2017; 4 (2): E58 111 http://doi.org/10.4038/jpgim.8150 2 Introduction Hypertension is a well-known cardiovascular disease with multi-organ involvement. It is one of the modifiable risk factors for coronary artery disease. The burden of hypertension in the world, as well as in the South Asian population, continues to rise as a result of demographic transition. In turn, hypertension based cardiovascular mortality and morbidity is increasing adding to the health burden of non-communicable disease. The representative value of an individual’s blood pressure (BP) should be critically evaluated because prognosis is dependent on achievement of BP control targets [1]. A wide variation in BP values has been observed with different techniques of BP measurement. However, diurnal BP profile is best evaluated by automated noninvasive ambulatory BP monitoring [2]. Ambulatory blood pressure monitoring (ABPM) has extended our capacity to identify the finer variations in the circadian rhythm of BP of an individual. It acts as a versatile tool for the assessment of BP in existing practice. It is particularly valuable in identifying whitecoat and masked hypertension and nocturnal dipping patterns which are key determinants of cardio-vascular outcomes [3]. None of the above parameters can be derived from clinic BP measurements. Several studies have highlighted the fact that patients with abnormal nocturnal BP dipping have a higher cardiovascular morbidity and mortality [4]. Novel evidence relating to circadian BP fluctuations has revealed that such adverse patterns correlate directly with coronary artery and cerebrovascular disease [5]. ABPM has been found to be a valuable research tool as well as a better prognostic tool in various study settings [6]. The aim of the present study was to explore the circadian pattern of BP variation, identify groups at risk for adverse cardiovascular outcomes and compare clinic BP measurements with ABPM in patients on treatment for essential hypertension. Methods A total of 100 patients were recruited to the study using convenient sampling. Inclusion criteria were patients who were above 18 years with stage I to III [7] hypertension with normal renal function as assessed by serum creatinine, blood urea, estimated glomerular filtration rate and having no previous history of coronary or cerebrovascular events. Patients with essential hypertension complicating pregnancy were excluded from the study. Each patient was clinically evaluated independently by two Senior Registrars in Cardiology with a detailed history and physical examination, including pulse rate, blood pressure in both arms, cardiac auscultation and physical signs suggestive of secondary hypertension. Socio-demographic data, a history of putative vascular risk factors, past medical history and the results of recent laboratory investigations were obtained. Twenty-four-hour Journal of the Postgraduate Institute of Medicine 2017; 4 (2): E58 111 http://doi.org/10.4038/jpgim.8150 3 ABPM was performed, and the patients underwent electrocardiography and twodimensional echocardiographic assessment performed independently by two cardiology senior registrars. Manual BP measurement was performed according to a standard protocol [8]. Informed written consent was obtained from all participants. The study protocol was approved by the Research and Ethical Review Committee, General Hospital (Teaching) Kandy, Sri Lanka. Ambulatory Blood Pressure Monitoring Twenty-four hour ABPM measurements in the non-dominant arm were obtained using one portable oscillometric monitor (Contec ABPM 50®). This ABPM device achieves the standards of the American National Standards Institute. The patients were allowed to engage in their regular activities of daily living and advised to abstain from vigorous physical activity during the monitoring period. Night time was defined as 2201h to 0500h and daytime was defined as between 0501h and 2200h. The pressure monitoring device was programmed to read the BP every 30 minutes from 0501h to 2200h and every 60 minutes from 2201h to 0500h. Definition of the parameters of day and night BP variations In the clinic, using manual BP measurement, a reading of ≥140mmg Hg and/or ≥90 mm Hg was taken as indicative of hypertension. Twenty-four-hour AMBP cut-offs were taken as ≥130 mm Hg and/or≥80 mm Hg [2]. Day time AMBP cut-offs were taken as ≥135 mm Hg and/or≥85 mm Hg whereas night time AMBP cut offs were set at ≥120 mm Hg and/or≥70 mm Hg [2]. All AMBP cut-off values are lower than those used for manual BP as AMBP calculates mean BP over a period of time rather than at a single time point as for clinic BP. The night-to-day BP ratio was calculated using average nocturnal and daytime BP. Dipping was defined by the night-to-day BP ratio; mild dipping (0.9 <ratio <1.0); dipping (0.8 < ratio <0.9); and extreme dipping (ratio <0.8) [2]. Night time rise of BP (i.e. reverse dipping) was defined as a ratio >1.0 [8]. Morning surge was defined as a difference of the morning blood pressure during the first 2 hours after awakening and the average of the lowest nighttime BP [9]. Heart rate nondippers were defined as those who showed a reduction in heart rate less than 10% between day and night [10]. Statistical tests SPSS version 17.0 was used for data entry and analysis. The statistical significance of continuous variables between the subgroups was evaluated using the student t-test and variation between categorical variables was evaluated by the x square test. A p value of <0.05 or confidence limit of 95 % was considered as significant. Journal of the Postgraduate Institute of Medicine 2017; 4 (2): E58 111 http://doi.org/10.4038/jpgim.8150 4 Results Demographic data and blood pressure profile There were 100 subjects in the study sample with 28% (n=28) males and 72% (n=72) females. The mean age of the sample was 61±9 years. Baseline characteristics, comorbidities and pharmacotherapy are described in Table 01. The ABPM profile of the sample is illustrated in Table 02. Table 1: Characteristics of the study group Characteristic Result N(%) Age in years (mean ± SD) 60.9±8.7 Gender Male 28(28) Female 72 (72) Co-morbidities N (%) Diabetes Mellitus 25 (25) Dyslipidemia 62 (62) Pharmacotherapy N (%) ACEIs/ARBS 81 (81)


Introduction
Hypertension is a well-known cardiovascular disease with multi-organ involvement.It is one of the modifiable risk factors for coronary artery disease.The burden of hypertension in the world, as well as in the South Asian population, continues to rise as a result of demographic transition.In turn, hypertension based cardiovascular mortality and morbidity is increasing adding to the health burden of non-communicable disease.
The representative value of an individual's blood pressure (BP) should be critically evaluated because prognosis is dependent on achievement of BP control targets [1].A wide variation in BP values has been observed with different techniques of BP measurement.However, diurnal BP profile is best evaluated by automated noninvasive ambulatory BP monitoring [2].Ambulatory blood pressure monitoring (ABPM) has extended our capacity to identify the finer variations in the circadian rhythm of BP of an individual.It acts as a versatile tool for the assessment of BP in existing practice.It is particularly valuable in identifying whitecoat and masked hypertension and nocturnal dipping patterns which are key determinants of cardio-vascular outcomes [3].None of the above parameters can be derived from clinic BP measurements.
Several studies have highlighted the fact that patients with abnormal nocturnal BP dipping have a higher cardiovascular morbidity and mortality [4].Novel evidence relating to circadian BP fluctuations has revealed that such adverse patterns correlate directly with coronary artery and cerebrovascular disease [5].ABPM has been found to be a valuable research tool as well as a better prognostic tool in various study settings [6].
The aim of the present study was to explore the circadian pattern of BP variation, identify groups at risk for adverse cardiovascular outcomes and compare clinic BP measurements with ABPM in patients on treatment for essential hypertension.

Methods
A total of 100 patients were recruited to the study using convenient sampling.Inclusion criteria were patients who were above 18 years with stage I to III [7] hypertension with normal renal function as assessed by serum creatinine, blood urea, estimated glomerular filtration rate and having no previous history of coronary or cerebrovascular events.Patients with essential hypertension complicating pregnancy were excluded from the study.
Each patient was clinically evaluated independently by two Senior Registrars in Cardiology with a detailed history and physical examination, including pulse rate, blood pressure in both arms, cardiac auscultation and physical signs suggestive of secondary hypertension.Socio-demographic data, a history of putative vascular risk factors, past medical history and the results of recent laboratory investigations were obtained.Twenty-four-hour ABPM was performed, and the patients underwent electrocardiography and twodimensional echocardiographic assessment performed independently by two cardiology senior registrars.Manual BP measurement was performed according to a standard protocol [8].Informed written consent was obtained from all participants.The study protocol was approved by the Research and Ethical Review Committee, General Hospital (Teaching) Kandy, Sri Lanka.Ambulatory Blood Pressure Monitoring Twenty-four hour ABPM measurements in the non-dominant arm were obtained using one portable oscillometric monitor (Contec ABPM 50®).This ABPM device achieves the standards of the American National Standards Institute.
The patients were allowed to engage in their regular activities of daily living and advised to abstain from vigorous physical activity during the monitoring period.Night time was defined as 2201h to 0500h and daytime was defined as between 0501h and 2200h.The pressure monitoring device was programmed to read the BP every 30 minutes from 0501h to 2200h and every 60 minutes from 2201h to 0500h.

Definition of the parameters of day and night BP variations
In the clinic, using manual BP measurement, a reading of ≥140mmg Hg and/or ≥90 mm Hg was taken as indicative of hypertension.Twenty-four-hour AMBP cut-offs were taken as ≥130 mm Hg and/or≥80 mm Hg [2].Day time AMBP cut-offs were taken as ≥135 mm Hg and/or≥85 mm Hg whereas night time AMBP cut offs were set at ≥120 mm Hg and/or≥70 mm Hg [2].All AMBP cut-off values are lower than those used for manual BP as AMBP calculates mean BP over a period of time rather than at a single time point as for clinic BP.
Morning surge was defined as a difference of the morning blood pressure during the first 2 hours after awakening and the average of the lowest nighttime BP [9].Heart rate nondippers were defined as those who showed a reduction in heart rate less than 10% between day and night [10].
Statistical tests SPSS version 17.0 was used for data entry and analysis.The statistical significance of continuous variables between the subgroups was evaluated using the student t-test and variation between categorical variables was evaluated by the x 2 square test.A p value of <0.05 or confidence limit of 95 % was considered as significant.

Results
Demographic data and blood pressure profile There were 100 subjects in the study sample with 28% (n=28) males and 72% (n=72) females.The mean age of the sample was 61±9 years.Baseline characteristics, comorbidities and pharmacotherapy are described in Table 01.The ABPM profile of the sample is illustrated in Table 02.

Figure 3: State of hypertension control by ABPM versus manual office BP monitoring
The agreement between the clinic BP and ABPM for diagnosing controlled or uncontrolled BP was low (58%, Kappa = 0.23).

Discussion
The use of ABPM devices is increasingly encountered in the management of hypertensive patients.The advantage of this technique is the provision of a better understanding of the diurnal variation in BP compared to static clinic BP measurements.Often, abnormalities in the biological rhythm of BP in an individual are not given importance or consideration when managing hypertension in a busy clinic.The present study was aimed at studying the behavior of diurnal BP in essential hypertensives as well as to compare the diagnostic strength of office BP with ABPM in our local health setting.

Variation of day time and nocturnal blood pressure
The study highlights that there is a statistically significant difference between nocturnal BP compared to daytime BP suggesting that decision making dependent on daytime office BP in the outpatient setting may give an inaccurate verdict on the actual BP control of an individual.This element has been highlighted in several other studies as well [8].In this study, the patients were advised to abstain from vigorous physical activity since that can give rise to high blood pressure values which may markedly affect the diurnal variation.This instruction helped to eliminate the confounding effect of exercise induced high day time blood pressure in the study sample.

Nocturnal dipping
Evidence is mounting that nocturnal high BP, blunting of nocturnal dipping and increased morning surge of BP contribute to adverse cardiovascular outcomes and end organ damage [11].Multiple sources of evidence propose an association between adverse cardiovascular outcomes such as acute MI and cerebrovascular events and altered circadian BP pattern [5].Additionally, many studies suggest that suboptimal nocturnal BP dipping can result in a variety of complications associated with elevated cardiac morbidity and mortality [12,13,4].The present study revealed that a majority of patients with hypertension have abnormal dipping.It is likely that these patients have an elevated risk of vascular complications such as myocardial infarction and stroke.Therefore, this special group needs more attention and close control of vascular risk factors to prevent future adverse cardiovascular outcomes.
The difference between the behavior of dippers and non-dippers and its association to prognosis is an emerging field in the dynamic BP era.In our study, the dippers were not different to non-dippers in their 24-hour average SBP or DBP.Also, there was no difference in their daytime average SBP or DBP.However, they differed by their nocturnal average SBP and DBP.Similar nocturnal variation had been reported in a study done by Seo W.S et al. [8].This observation strengthens the importance of the contribution of nocturnal hypertension in hypertensive patients.According to our study, the majority had nocturnal hypertension which would not be discovered by office BP.
There was no difference in the 24-hour average HR, daytime average HR or nocturnal average HR among dippers and non-dippers, in our study.It has been observed in one study that the daytime heart rate is lower in non-dippers than dippers [8].This suggests that dippers and non-dippers should be identified as different subgroups having their own clinical characteristics, and different prognostic pathways.This reinforces the importance of ABPM in hypertensive patients to identify their prognostic category.
Reverse dipping and early morning fluctuation of BP Cuspidi et al. [14] have revealed that a persistent non-dipper pattern is linked with an increased left ventricular mass index, a thicker interventricular septum and enlarged left atrium and the aortic root in previously untreated hypertensive patients.It will be interesting to determine the changes that occur in reverse dippers.
There is mounting evidence connecting early morning rise in BP and augmented cardiovascular risk [15].Though the mechanisms underlying this observation are not identified, many neurohumoral mechanisms may be responsible.Reverse dippers have been shown to display a broader range of pulse pressure at night than any other groups signifying the probable role of arterial stiffness as a contributing mechanism for their elevated adverse cardiovascular risk [1].ABPM may assist the physician to identify such specific high risk groups for more intensive control.Our study was able to identify that one quarter of the sample had a reverse dipping pattern suggesting it is not uncommon in our health practice.

Antihypertensive therapy and individualized decision making
There is some evidence that non-dippers may have a different response to antihypertensive pharmacotherapy than normal dippers suggesting that they are difficult to treat by conventional therapy [16].
There is also some evidence that antihypertensive pharmacotherapy may blunt the nocturnal rise in non-dippers and reverse dippers [17].This may vary according to the type of antihypertensive drug as well as the timing of drug dose [18].

Conclusion and Recommendations
Our study highlights the importance of individualized therapy for hypertension based on the diurnal BP profile of an individual rather than merely achieving a therapeutic target.
The study shows that this is applicable even to patients in a resource poor setting.
We recommend that physicians practice ABPM more frequently since it produces a better picture of an individual's overall blood pressure status.If cost is a limiting factor, the test should be performed in selected cases such as in patients where it is difficult to achieve BP targets.Further studies to explore the blood pressure variation and response among our hypertensive patients is encouraged.

Limitations
A limitation of our study is the convenient sampling method.Since we excluded patients with coronary artery disease, females were over represented.Subgroup analysis i.e. patients with diabetes mellitus, obesity, antihypertensive class etc. was not possible due to a relatively small sample size.

Figure 1 :Figure 2 :
Figure 1: Mean SBP by manual office BP versus Mean SBP by ABPM

Figure 4 :
Figure 4: Distribution of dipping pattern