Prevalence of sympathetic overactivity in hypertensive patients – A pan India, non-interventional, cross sectional study

1. Introduction

The seventh report of the joint national committee (JNC7) on prevention, detection, evaluation, and treatment of high blood pressure defines hypertension as blood pressure (BP) ≥ 140/90 mmHg. Hypertension affects nearly 1 billion of the global adult population and 26.4% of the adult population in 2000 had hypertension. The projected prevalence rate is 29.2% with absolute no. of 1.56 billion by 2025.¹ Though there is a lack of systemic data on prevalence of hypertension in India, pooling of many epidemiological studies reveals that hypertension is prevalent in 25% of urban and 10% of rural subjects.² Hypertension is one of the most important independent predictor of cardiovascular disease and cerebrovascular events. It accounts for an estimated 54% of all strokes and 47% of all ischemic heart disease events globally.³

Blood pressure is regulated by a complex interaction between various physiological systems and among them it is well established that Sympathetic Nervous System (SNS) plays a vital role. The last decade has seen a new and more complex picture emerging of the SNS as a key controller of the cardiovascular system under a variety of situations.⁵ Sympathetic overactivity (SO) plays an important role in the development of both hypertension and its related cardiovascular disorders.⁴ SO causes an increase in heart rate, cardiac output, peripheral vascular resistance, and sodium reabsorption in the kidney and a consequent elevation of systemic BP (Fig. 1).⁵ It is also found to be associated with prolongation of cardiac repolarisation time in hypertensive patients with morning BP peaks. It may play a critical role in increasing cardiovascular risk in such patients.⁶ SO in hypertension is also conducive to coronary heart disease through its association with high hematocrit values and excessive platelet agreeability.⁷

Fig. 1.

Influence of sympathetic overactivity on various systems.

In the given context of the role of SO in hypertension and the associated CV risk there is an acute need to study the prevalence of SO in India. Also it is extremely important to clearly identify symptoms of SO in patients with newly-diagnosed essential hypertension so that proper measures can be instituted early enough to control the same. The primary aim of this study was to assess the prevalence of SO in patients with newly diagnosed primary hypertension.

2. Materials and methods

Study Design: This is a multi centre, non interventional, cross sectional, pan India epidemiological study to estimate the prevalence of SO in patients with newly diagnosed essential hypertension. Data collection for each subject took place at three visits, with a gap of four weeks between each visit. Treatment including lifestyle modification and anti-hypertensives was at the discretion of the treating physician during the study. The assignment of a subject to a particular therapeutic strategy was not decided in advance by a protocol but fell within current clinical practice. Commercially available anti-hypertensive drugs were used during this study.

The study was conducted in accordance with the International Conference on Harmonisation-Good Clinical Practice (ICH GCP) guidelines and the ethical code of conduct laid out by declaration of Helsinki and Indian Council of Medical Research (ICMR) guidelines. Written informed consent was taken from all participating subjects. The study was approved by Clinicom, an independent ethics committee in Bangalore. Drug Controller General of India (DCGI) was notified as per existing regulatory requirement in India. The study was registered with ClinicalTrials.gov (NCT01295021). Due to the non-interventional nature of this study, though no pro-active safety data was collected, spontaneous safety events were reported.

Inclusion and exclusion criteria are listed below in Table 1.

Table 1.

Inclusion and exclusion criteria.

Inclusion criteria	Exclusion criteria
•Men and women aged ≥18 years of age with newly diagnosed primary hypertension (SBP ≥ 140 mmHg, DBP ≥ 90 mmHg as per JNC 7 Criteria) will be eligible for the study. •Provision of subject informed consent	•History of coronary artery disease
	•History of diabetes
	•History of malignancy
	•Current active liver disease or ALT levels >3 times the upper Limit of Normal (ULN).
	•Unexplained creatine kinase (CK) levels > 10 times ULN.
	•History of chronic kidney disease
	•Uncontrolled hyperthyroidism
	•History of alcohol or drug abuse within the last 5 years
	•Initiation of hormone – replacement therapy or oral contraceptives within 3 months of enrollment.
	•Currently on treatment with any drug which can affect BP or resting heart rate
	•Pregnant or breastfeeding women
	•Refusal to sign informed consent forms
	•If participating in any clinical trial, the subject cannot take part in this study

Statistical Analyses: Descriptive statistics was used for all demographic variables. Statistical hypothesis testing using chi square test and likelihood ratio chi-square test were conducted to find out whether any statistically significant association exists between the variables tested. 5% level of significance was considered as statistically significant. T-test was performed to test the significance of association between mean change in systolic and diastolic blood pressure and mean change in heart rates from first visit to third visit.

3. Results

The study was carried out on 1514 newly diagnosed hypertensive patients (63.58% males, 35.62% females). The baseline data is presented in Table 2. The Body Mass Index (BMI) observations in the study were grouped according to the Indian guidelines issued by Ministry of Health.⁸ Among the study population for whom BMI could be calculated, 65.07% belonged to the ‘Obese’ category, and another 18.51% to the ‘Overweight’ category. In the study we observed that 18.02% of the patients were smokers and 47.44% had a family history of hypertension.

Table 2.

Baseline characteristics.

Variable	Mean
Age (yrs)	47.94
Height (cm)	163.25
Weight (kg)	71.29
BMI (kg/m2)	27.29

Of the 1514 subjects, 945 had symptoms of SO and thus the prevalence of SO in the study population was 62.42% Table 3 gives a detailed distribution of the different symptoms of SO observed by investigators in this study. A patient may have more than one symptom of SO and therefore there could be overlaps in the data. We observed 43.20%, 29.52%, 22.19% and 12.09% of the study population had symptoms of restlessness, inappropriate sweating, tremor in hands and fast speech respectively.

Table 3.

Proportion of study population with various symptoms of SO.

Sympathetic overactivity
Symptoms	n (%)
Restlessness	654 (43.20)
Inappropriate sweating	447 (29.52)
Tremors in hands	336 (22.19)
Fast speech	183 (12.09)

Blood pressure and heart rate data at first visit was available for 1514 and 1502 patients respectively. The mean systolic BP, diastolic BP and heart rate were 160.33 mmHg, 97.29 mmHg and 90.12 beats per minute (bpm) respectively. Table 4 provides the details for all the three study visits in terms of BP and HR.

Table 4.

BP and HR during the study period.

BP/HR	Visit	n	Mean (SD)
BP – systolic	Visit 1	1514	160.33 (14.64)
	Visit 2	1506	142.89 (12.67)
	Visit 3	1501	133.09 (10.44)
BP – diastolic	Visit 1	1514	97.29 (7.12)
	Visit 2	1506	87.82 (6.13)
	Visit 3	1501	82.88 (5.27)
Heart rate	Visit 1	1502	90.12 (10.41)
	Visit 2	1488	81.95 (7.89)
	Visit 3	1479	77.43 (6.74)

The mean change in systolic and diastolic blood pressure and Heart rate between first and second visits, second and third visits and first and third visits have been tabulated in Table 5. Overall, the trend shows a good control in the management of hypertension and heart rate.

Table 5.

Mean change in systolic and diastolic blood pressures and Heart Rate across visits.

Variable	Visit	n	Mean (SD)
bp – systolic	Visit 1–2	1506	−17.69 (13.28)
	Visit 2–3	1499	−9.65 (8.9)
	Visit 1–3	1501	−27.34 (14.31)
BP – diastolic	Visit 1–2	1506	−9.48 (7.3)
	Visit 2–3	1499	−4.95 (5.56)
	Visit 1–3	1501	−14.43 (7.75)
Heart rate	Visit 1–2	1488	−8.21 (8.42)
	Visit 2–3	1474	−4.52 (6.22)
	Visit 1–3	1479	−12.74 (10.52)

We found a statistically significant association between heart rate and hypertension in all the three visits (p ≤ 0.0001). We also found out statistically significant association between SO and heart rate in first and second visits (p ≤ 0.0001) but not in the third visit. We found that majority (40.07%) of the patients who had symptoms of SO fall under the BMI category of ‘Obese’. However, we did not find any statistically significant association between SO and BMI or age.

We also studied the association between SO and hypertension across all three visits. In the first and third visits we did not find any statistically significant association, however, a significant association (p = 0.0125) was observed in 2nd visit.

The most commonly prescribed anti-hypertensive drugs in the study population were Metoprolol alone, followed by Metoprolol in combination with Amlodipine, Amlodipine alone, Olmesartan alone, and Metoprolol in combination with Olmesartan. Fig. 2 represents the prescription of these drugs for all the three visits combined. The average reduction in systolic and diastolic blood pressure from the first to the third visit for patients on Metoprolol (n = 613) was 24.61 and 13.99 mmHg respectively. The average reduction in heart rate for this particular subpopulation was found to be 14.53 bpm. No serious adverse event was reported in this study.

Fig. 2.

Most commonly prescribed anti-hypertensive drugs.

4. Discussion

With increasing recognition about the role of SO in the pathophysiology of hypertension and associated cardiovascular complications, it is of utmost importance to address the need for generation of Indian data on the prevalence and management of SO in newly diagnosed hypertensives. In a country where one among four urban dwellers is a hypertensive and 70% of them in stage I hypertension, it is imperative to effectively control the BP and take proactive measures to minimize the associated CV risk. Our study result shows prevalence of SO in newly diagnosed hypertensive patients in India to be 62.42%.

This data is in line with data from Smith et al study which showed that central sympathetic activity was highest in borderline hypertension, early stage, and complicated essential hypertension, and this activity was likely to play an integral role in the development of hypertension and its complications.⁹

We now know that at least six out of ten newly diagnosed hypertensive patients in India have SO. We hypothesize a convergence in the management of hypertension through therapeutic intervention of SNS and cardiovascular system, and we believe this will be one of the emerging treatment targets in the near future. In clinical practice, physicians should look for symptoms like restlessness, inappropriate sweating and tremors in hands as indicators for SO while treating patients with hypertension. As our results suggest, these were the highest reported symptoms in patients with SO. Our results point towards the correlation between SO and heart rate and also between SO and hypertension. Our study results will encourage physicians to take a more proactive role in identifying and managing SO for improved cardiovascular outcomes in newly diagnosed hypertensives.

We must admit that this research has some limitations. Due to the real world setting of the study, we had few patients lost to follow up, some drop outs and therefore unavailability of the same pool of patients for all the analysis of different parameters. Though a controlled clinical trial would have helped address these challenges, as our aim was to obtain real world Indian data in a cross sectional setting, we opted for this study design. While we do acknowledge the study limitations, we believe the outcome is still invaluable in the context of SO and hypertension in India. Further research is necessary to arrive at concrete causal and mechanistic relationships between the two. We hope that our research will pave the way for more such initiatives.

Conflicts of interest

All authors have none to declare.