Background: Chronotherapy in hypertension control is considered to better control nocturnal blood pressure patterns. This study aimed at studying relation between diurnal blood pressure patterns and timing of antihypertensive medication. Method: Hypertensive patients of age group 19 years to 65 years who were on antihypertensives for a minimum period of one month and were free of any cardiovascular complication or chronic kidney disease were included in the study. After doing routine workup, they were subjected to 24-hour ambulatory blood pressure monitoring. Results: In this study of 105 patients (mean age 44±10.9), morning administration of antihypertensive medication resulted in significantly higher blood pressure surges and less nighttime BP decrease compared to nighttime administration, with a p-value of 0.001. No significant difference was found across medication classes for nocturnal dipping. Conclusion: Taking antihypertensive drugs in night appears to results in better control of hypertension.
Chronotherapy is a method of disease management which takes circadian rhythms of different organ systems into account for better control of illness. It aligns various therapies in lines with physiological diurnal drive of the body.1 With the advent of ambulatory blood pressure monitoring devices, concept of chronotherapy has become popular in management of hypertension. Nocturnal blood pressure, nocturnal fall in blood pressure and morning surge in blood pressure is of specific interest as these are associated with adverse cardiovascular events.2 As per Europeon society for hypertension guidelines, Dippers are the ones with systolic blood pressure dip of >10% during sleeping time. This is associated with lesser cardiovascular risk. Non dippers are the ones with systolic blood pressure dip of <10%. Extreme-Dippers are the patients with nocturnal dip of >20 % during sleep time. Reverse Dippers are the patients with dip of <0% during sleep. Non dippers, reverse dippers ,extreme dippers and early morning blood pressure surge are associated with adverse cardiovascular outcomes.3 Masked hypertension is defined by presence of hypertension on ambulatory blood pressure monitoring but absent in office blood pressure readings and is associated with adverse cardiovascular outcomes.4 The aim of this study was to study role of chronotherapy in management of diurnal hypertension patterns.
This was a cross sectional observational study of patients who presented in the OPD of Department of Medicine in Sri Guru Ram Das Institute of Medical Sciences and Research, Sri Amritsar from 01st January 2023 to 30 march 2024 and diagnosed with hypertension and were on antihypertensive drugs. Patients with Coronary artery disease, Chronic Kidney Disease, Cardiomyopathy, Congenital Heart Disease, Valvular Heart Disease and Cardiac failure were excluded. A written informed consent was taken from all the consenting patients included in study population. A detailed history of each patient was taken including demographic data (current age, age at the time of diagnosis, gender, occupation, residence), history of presenting symptoms, precomorbid conditions, risk factors of hypertension and the patient’s treatment history followed by detailed clinical examination with specific reference to end organ damage secondary to uncontrolled hypertension. Three reading of office BP were taken according to standard protocol and average of three BP reading will be recorded. Then the patients were subjected to 24 hour Ambulatory BP monitoring using ABPM50 device by Contec Medical Systems. BP cuff was tied around left upper arm with monitor held hanging around waist side from shoulder with a strap. A standard software provided by contec medical system was used to upload and download data from ABPM50. Average office systolic/diastolic blood pressure were compared with average 24 hours systolic/diastolic ambulatory blood pressure. Parameters of ABPM including 24 hour SBP and DBP, mean daytime SBP and DBP, mean night time SBP and DBP , day time and night time SBP and DBP load were analysed and compared with type of antihypertensive and timing of hypertensive.
Parameters of morning surge in blood pressure were calculated as:
Statistical Analysis
Data was recorded in a Microsoft excel spread sheet and analysed using Statistical Package for the IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp., Chicago Continuous data was presented as mean with standard deviation. Categorical data was expressed as percentages. Numerical variables were normally distributed and analysed using independent t- test and Oneway ANOVA test. Categorical variables were analysed using chi square test. P- value less than 0.05 was taken as statistically significant.
The results were analysed and compared to previous studies to draw relevant conclusions.
Table1: Distribution of study population according to age distribution
Age group (years) |
No. of cases (n=105) |
%age |
19-45 |
49 |
46.7 |
45-65 |
56 |
53.3 |
Total |
105 |
100.0 |
In the present study, total of 105 patients were enrolled. 49 patients were in 19-45 years age group comprising 46.7%. 56 patients were in 46-65 years age group comprising 53.3%. The mean age was 44.9±10.9 years.
Figure 1: Distribution of study population according to age distribution
Table 2: Distribution of study population according to gender
Gender |
No. of cases |
%age |
Females |
47 |
44.8 |
Males |
58 |
55.2 |
Total |
105 |
100.0 |
In present study, 47 patients were females constituting 44.8% of the study population and 58 patients were females constituting 55.2% of the study population.
Figure 2:- Distribution of study population according to gender
Table 3: Distribution of study population according to timing of antihypertensive and its relation with mean sleep trough SBP surge
Timing of antihypertensive |
No. |
Sleep trough morning SBP surge |
p-value |
|
Mean |
SD |
|||
Morning |
60 |
22.4543 |
6.74010 |
0.001 |
Night |
45 |
6.5639 |
5.50902 |
|
Total |
105 |
15.9112 |
10.83595 |
In this study examining the timing of antihypertensive medication, the sleep trough morning systolic blood pressure (SBP) surge was observed in two groups. The Morning group (60 participants) had a mean SBP surge of 22.4543 (SD = 6.74010), while the Night group (45 participants) had a mean SBP surge of 6.5639 (SD = 5.50902). The total sample size was 105, with an overall mean SBP surge of 15.9112 (SD = 10.83595). The p-value for the difference between the two groups was 0.001.
Figure 3: Distribution of study population according to timing of antihypertensive and its relation with mean sleep trough SBP surge
Table 4: Distribution of study population according to timing of antihypertensive and its relation with sleep trough morning DBP surge
timing of antihypertensive |
No. |
Sleep trough morning DBP surge |
p-value |
|
Mean |
SD |
|||
Morning |
60 |
16.525 |
7.809 |
0.001 |
Night |
45 |
6.296 |
5.838 |
|
Total |
105 |
12.213 |
7.879 |
In this study examining the timing of antihypertensive medication, the sleep trough morning diastolic blood pressure (DBP) surge was observed in two groups. The Morning group (60 participants) had a mean DBP surge of 16.525 (SD = 7.809), while the Night group (45 participants) had a mean DBP surge of 6.296 (SD = 5.838). The total sample size was 105, with an overall mean DBP surge of 12.213 (SD = 7.879). The p-value for the difference between the two groups was 0.001.
Figure 4: Distribution of study population according to timing of antihypertensive and its relation with sleep trough morning DBP surge
Table 5: Distribution of study population according to timing of antihypertensive and its relation with preawakening SBP surge
timing of antihypertensive |
No. |
Preawakening SBP surge |
p-value |
|
Mean |
SD |
|||
Morning |
60 |
13.766 |
6.690 |
0.001 |
Night |
45 |
3.818 |
4.718 |
|
Total |
105 |
8.563 |
6.918 |
In this study examining the timing of antihypertensive medication, the preawakening systolic blood pressure (SBP) surge was observed in two groups. The Morning group (60 participants) had a mean SBP surge of 13.7636 (SD = 6.6395), while the Night group (45 participants) had a mean SBP surge of 3.818 (SD = 4.718). The total sample size was 105, with an overall mean SBP surge of 8.563 (SD = 6.918). The p-value for the difference between the two groups was 0.001.
Figure 5: Distribution of study population according to timing of antihypertensive and its relation with preawakening SBP surge
Table 6: Distribution of study population according to timing of antihypertensive and its relation with preawakening DBP surge
timing of antihypertensive |
No. |
Preawakening DBP surge |
p-value |
|
Mean |
SD |
|||
Morning |
60 |
9.446 |
6.925 |
0.001 |
Night |
45 |
2.2139 |
4.660 |
|
Total |
105 |
7.166 |
6.221 |
In this study examining the timing of antihypertensive medication, the preawakening diastolic blood pressure (DBP) surge was measured in two groups. The Morning group (60 participants) had a mean DBP surge of 9.446 (SD = 6.925), while the Night group (45 participants) had a mean DBP surge of 2.2139 (SD = 4.660). The total sample size was 105, with an overall mean preawakening DBP surge of 7.166 (SD = 6.221). The p-value for the difference between the two groups was 0.001.
Figure 6: Distribution of study population according to timing of antihypertensive and its relation with preawakening DBP surge
Table 7: Distribution of study population according to timing of antihypertensive and its relation with rising morning SBP surge
timing of antihypertensive |
No. |
Rising morning SBP surge |
p-value |
|
Mean |
SD |
|||
Morning |
60 |
10.291 |
12.072 |
0.003 |
Night |
45 |
3.213 |
6.421 |
|
Total |
105 |
7.911 |
11.827 |
In this study investigating the timing of antihypertensive medication, the rising morning systolic blood pressure (SBP) surge was assessed in two groups. The Morning group (60 participants) had a mean SBP surge of 10.291 (SD = 12.072), while the Night group (45 participants) had a mean SBP surge of 30213 (SD = 6.421). The total sample size was 105, with an overall mean SBP surge of 7.911 (SD = 11.827). The p-value for the difference between the two groups was 0.003.
Figure 7: Distribution of study population according to timing of antihypertensive and its relation with rising morning SBP surge
Table 8: Distribution of study population according to timing of antihypertensive and its relation with rising morning DBP surge
timing of antihypertensive |
No. |
Rising morning DBP surge |
p-value |
|
Mean |
SD |
|||
Morning |
60 |
9.217 |
11.678 |
0.001 |
Night |
45 |
1.312 |
6.621 |
|
Total |
105 |
6.857 |
10.401 |
In this study on the timing of antihypertensive medication, the rising morning diastolic blood pressure (DBP) surge was examined in two groups. The Morning group (60 participants) had a mean DBP surge of 9.217 (SD = 11.678), while the Night group (45 participants) had a mean DBP surge of 1.312 (SD = 6.621). The total sample size was 105, with an overall mean DBP surge of 6.857 (SD = 10.401). The p-value for the difference between the two groups was 0.001.
Figure 8: Distribution of study population according to timing of antihypertensive and its relation with rising morning DBP surge
Table 9: Distribution of study population according to timing of antihypertensive and its relation with night decrease SBP
timing of antihypertensive |
No. |
Night decrease SBP |
p-value |
|
Mean |
SD |
|||
Morning |
60 |
5.712 |
4.261 |
0.001 |
Night |
45 |
9.924 |
6.143 |
|
Total |
105 |
7.322 |
5.019 |
In this study on the timing of antihypertensive medication, the decrease in systolic blood pressure (SBP) during the night was analyzed in two groups. The Morning group (60 participants) had a mean decrease in SBP of 5.712 (SD = 4.261), while the Night group (45 participants) had a mean decrease in SBP of 9.924 (SD = 6.143). The total sample size was 105, with an overall mean decrease in SBP of 7.322 (SD = 5.019). The p-value for the difference between the two groups was 0.001.
Figure 9: Distribution of study population according to timing of antihypertensive and its relation with night decrease SBP
Table 10: Distribution of study population according to timing of antihypertensive and its relation with night decrease DBP
timing of antihypertensive |
No. |
Night decrease DBP |
p-value |
|
Mean |
SD |
|||
Morning |
60 |
2.06 |
0.631 |
0.001 |
Night |
45 |
2.70 |
0.762 |
|
Total |
105 |
2.34 |
0.620 |
In this study on the timing of antihypertensive medication, the decrease in diastolic blood pressure (DBP) during the night was measured in two groups. The Morning group (60 participants) had a mean decrease in DBP of 2.06 (SD = 0.631), while the Night group (45 participants) had a mean decrease in DBP of 2.70 (SD = 0.762). The total sample size was 105, with an overall mean decrease in DBP of 2.34 (SD = 0.620). The p-value for the difference between the two groups was 0.001.
Figure 10: Distribution of study population according to timing of antihypertensive and its relation with night decrease DBP
Table 11: Distribution of study population according number of antihypertensives and its relation to mean night decrease in SBP
No. of drugs |
No. |
Night decrease SBP |
p-value |
|
Mean |
SD |
|
||
1 |
38 |
7.411 |
5.122 |
0.522 |
2 |
62 |
7.851 |
5.022 |
|
3 |
3 |
4.400 |
3.941 |
|
4 |
2 |
16.900 |
6.991 |
|
Total |
105 |
7.378 |
5.949 |
In this study examining the number of antihypertensive drugs and their effect on the nighttime decrease in systolic blood pressure (SBP), 67 participants using one drug had a mean nighttime SBP decrease of 7.411 (SD = 5.122), 35 participants using two drugs had a mean nighttime SBP decrease of 7.851 (SD = 5.022), 3 participants using three drugs had a mean nighttime SBP decrease of 4.400 (SD = 3.3941), and 2 participant using four drugs had a nighttime SBP decrease of 16.900 (SD = 6.991),. The total sample size was 105, with an overall mean nighttime SBP decrease of 7.378 (SD = 5.949). The p-value for the difference between the groups was 0.522.
Figure 11: Distribution of study population according number of antihypertensives and its relation to mean night decrease in SBP
Table 12: Distribution of study population according number of antihypertensives and its relation to mean night decrease in DBP
No. of drugs |
No. |
Night decrease DBP |
p-value |
|
Mean |
SD |
|
||
1 |
38 |
8.172 |
7.410 |
0.425 |
2 |
62 |
10.027 |
7.424 |
|
3 |
3 |
6.450 |
7.610 |
|
4 |
2 |
17.6 |
7.902 |
|
Total |
105 |
9.816 |
7.913 |
In this study examining the number of antihypertensive drugs and their effect on the nighttime decrease in diastolic blood pressure (DBP), 62 participants using one drug had a mean nighttime DBP decrease of 10.027 (SD = 7.424), 38 participants using ONE drugs had a mean nighttime DBP decrease of 8.172 (SD = 7.410), 3 participants using three drugs had a mean nighttime DBP decrease of 6.450 (SD = 7.610) AND 2 participant using four drugs had mean night time DBP ecrease of 17.6 % (SD = 7.092) . The total sample size was 105, with an overall mean nighttime DBP decrease of 9.816 (SD = 7.913). The p-value for the difference between the groups was 0.425.
Figure 12: Distribution of study population according number of antihypertensives and its relation to mean night decrease in DBP
Table 13: Distribution of study population according to antihypertensive class and its relation with mean night decrease SBP
Class group |
No. |
SBP (%age decrease) |
p-value |
|
Mean |
SD |
|||
ARB/ACEI |
30 |
7.188 |
6.193 |
0.425 |
ARB + CCB |
35 |
7.233 |
6.520 |
|
ARB+BETA BLOCKER |
15 |
8.425 |
5.871 |
|
ARB+CCB+Diuretic |
3 |
8.100 |
4.445 |
|
ARB+Diuretic |
10 |
7.822 |
4.122 |
|
CCB |
8 |
5.767 |
8.591 |
|
CCB+ARB+Diuretic+BETA BLOCKER |
2 |
5.400 |
3.394 |
|
CCB+BETA BLOCKER |
2 |
16.900 |
3.952 |
|
TOTAL |
105 |
7.632 |
6.421 |
In this study examining the class of antihypertensive medication and the percentage decrease in systolic blood pressure (SBP), the following observations were made: ARB/ACEI group (30 participants) had a mean SBP decrease of 7.188% (SD = 6.193), ARB + CCB group (35 participants) had a mean SBP decrease of 7.233% (SD = 6.520), ARB + Beta Blocker group (15 participants) had a mean SBP decrease of 8.425% (SD = 5.871), ARB + CCB + Diuretic group (3 participant) had a mean SBP decrease of 8.100% (SD = 4.445), ARB + Diuretic group (10 participants) had a mean SBP decrease of 7.882% (SD = 4.445), CCB group (8 participants) had a mean SBP decrease of 5.767% (SD = 8.591), CCB + ARB + Diuretic + Beta Blocker group (2 participants) had a mean SBP decrease of 5.400% (SD = 3.394), and CCB + Beta Blocker group (2 participant) had a mean SBP decrease of 16.900% (SD = 3.952),. The total sample size was 105, with an overall mean SBP decrease of 7.632% (SD = 6.421). The p-value for the difference between the groups was 0.425.
Figure 13: Distribution of study population according to antihypertensive class and its relation with mean night decrease SBP
Table 14: Distribution of study population in relation to antihypertensive class and its relation with night decrease DBP
Class group |
No. |
DBP (%age decrease) |
p-value |
|
Mean |
SD |
|||
ARB/ACEI |
30 |
8.294 |
6.117 |
0.694 |
ARB + CCB |
35 |
9.262 |
7.926 |
|
ARB+BETA BLOCKER |
15 |
11.151 |
5.239 |
|
ARB+CCB+Diuretic |
3 |
12.25 |
5.339 |
|
ARB+Diuretic |
10 |
12.120 |
7.936 |
|
CCB |
8 |
8.222 |
8.907 |
|
CCB+ARB+Diuretic+BETA BLOCKER |
2 |
7.500 |
8.061 |
|
CCB+BETA BLOCKER |
2 |
17.600 |
8.002 |
|
TOTAL |
105 |
10.386 |
8.090 |
In this study examining the class of antihypertensive medication and the percentage decrease in diastolic blood pressure (DBP), the following observations were made: the ARB/ACEI group (30 participants) had a mean DBP decrease of 8.294% (SD = 6.117), the ARB + CCB group (35 participants) had a mean DBP decrease of 9.262% (SD = 7.926), the ARB + Beta Blocker group (15 participants) had a mean DBP decrease of 11.151% (SD = 5.239), the ARB + CCB + Diuretic group (3 participant) had a mean DBP decrease of 12.25% (SD = 5.339), the ARB + Diuretic group (10 participants) had a mean DBP decrease of 12.00% (SD = 7.936), the CCB group (8 participants) had a mean DBP decrease of 8.22% (SD = 8.907), the CCB + ARB + Diuretic + Beta Blocker group (2 participants) had a mean DBP decrease of 7.500% (SD = 8.061), and the CCB + Beta Blocker group (2 participant) had a mean DBP decrease of 17.600% (SD = 8.002). The total sample size was 105, with an overall mean DBP decrease of 10.386% (SD = 8.090). The p-value for the difference between the groups was 0.694.
Figure 14: : Distribution of study population in relation to antihypertensive class and its relation with night decrease DBP
Majority of cardiovascular adverse events occur due to abnormal nocturnal blood pressure patterns and morning blood pressure surge.5 These mainly happen due to abnormalities in sympathetic nervous system activity, salt and volume balance, and activation of the renin-angiotensin system.6 So, it is important to take into consideration the physiological aspects of blood pressure for better control f hypertension.7
In the present study, morning administration of antihypertensive medication resulted in higher sleep trough morning systolic blood pressure (SBP) surges (Morning: 22.4543 ± 6.7401 vs. Night: 6.5639 ± 5.5090) and diastolic blood pressure (DBP) surges (Morning: 16.525 ± 7.809 vs. Night: 6.296 ± 5.838) compared to nighttime administration. Pre awakening SBP surge (Morning: 13.776 ± 6.690 vs. Night: 3.818 ± 4.718) and DBP surge (Morning: 9.446± 6.925 vs. Night: 2.9193± 4.660) surges were also notably higher in the morning group. Additionally, morning administration correlated with a higher incidence of rising morning SBP (Morning: 10.219 ± 12.072vs. Night: 3.213 ± 6.421) and DBP (Morning: 9.217 ± 11.678 vs. Night: 1.312 ± 6.621) surges consistent with many other studies. A study by Xie Ziyan et al.8 to study the impact of chronotherapy on the morning surge of blood pressure, included 1,724 patients from 10 different trials. The results showed that taking antihypertensive drugs in the evening led to a significant reduction in the morning blood pressure surge (−5.30 mmHg, 95% CI −8.80 to -1.80), nighttime systolic blood pressure (SBP) (−2.29 mmHg, 95% CI −4.43 to −0.15), and nighttime diastolic blood pressure (DBP) (−1.63 mmHg, 95% CI −3.23 to −0.04. A study by Hermida Ramón C et al.9 was done to effect of chrontherapy on non dipping and increased asleep blood pressure. This meta-analysis of 155 studies and 23972 patients concluded that night time dosing of antihypertensive helps in reduction of night time blood pressure and morning surge of blood pressure and hence results in reduction of cardiovascular risk. Our findings were consistent with these studies.
In this study, significant differences were observed between morning and night dosing groups with respect to morning surge. The morning group (60 participants) had a mean nighttime systolic blood pressure (SBP) decrease of 5.712 mmHg (SD = 4.261), while the night group (45 participants) experienced a greater decrease of 9.924 mmHg (SD = 6.143), with a p-value of 0.001. For diastolic blood pressure (DBP), the morning group showed a mean decrease of 2.06 mmHg (SD = 0.631), compared to 2.700 mmHg (SD = 0.762) in the night group, also with a p-value of 0.001. Additionally, the number of antihypertensive drugs impacted nighttime BP decreases, with one drug resulting in a mean SBP decrease of 7.741 mmHg (SD = 5.122) and two drugs yielding a decrease of 7.185 mmHg (SD = 5.022), while DBP decreases varied similarly. Analysis by medication class showed no significant difference across the classes for nocturnal dipping. These results underscore the potential benefits of nighttime antihypertensive dosing in managing blood pressure. A study by Xie, Ziyan et al.8 to study the impact of chronotherapy on the morning surge of blood pressure, included 1,724 patients from 10 different trials. There was significant increase in nocturnal dipping with night dose of antihypertensive. A study by Hermida, Ramón C et al.9 showed that night dosing of antihypertensive results in significant increase in nocturnal dipping. Our findings were aligned with these studies highlighting importance of chronotherapy in control of hypertension.
Patients taking antihypertensive drug in night had significantly lower morning surge and higher nocturnal dipping as compared to those taking it in morning. So timing of antihypertensive is more important than number or class of antihypertensive and the concept of chronotherapy aligns action of antihypertensive drugs with diurnal rhythm of blood pressure .