ABSTRACT
Introduction
Re-establishing “dipping” physiology significantly reduces cardiovascular events. The aim was to investigate the effect of timing of fixed dose triple antihypertensive combinations on blood pressure (BP) control.
Methods
One hundred sixteen consecutive patients (62.7 ± 10.7 years, 38 men) with grade II hypertension were randomized into four groups. Group 1 and Group 2 patients were given angiotensin converting enzyme inhibitor-based triple antihypertensive pills to be taken in the morning or evening, respectively while Group 3 and Group 4 patients were given angiotensin receptor blocker (ARB) based triple antihypertensive pills to be taken in the morning or evening, respectively. All patients underwent 24-h ambulatory BP monitoring 1 month after the initiation of treatment.
Results
There were not any significant differences in the characteristics, BP values and loads among groups. All patients in each group had good BP control. Dipping pattern in systolic BP was observed significantly less in Group 3 patients taking ARB in the morning (3 patients) compared to other groups (12 patients) in each group, [P = .025]. Similarly, dipping pattern in diastolic BP was observed significantly less in Group 3 patients (4 patients) compared to others (13 patients) in Group 1 and 15 patients in Group 2 and Group 4, [P = .008]. Nondipping pattern was significantly associated with taking ARB in the morning, even when adjusted by age, sex, and other comorbidities.
Conclusion
Fixed dose triple antihypertensive drug combinations enable good BP control regardless of the timing of drug while ARB-based ones may be taken in the evening to ensure dipping physiology.
Introduction
Ambulatory blood pressure (ABP) monitoring is a method based on blood pressure (BP) measurements performed by the Holter device for 24 h a day, which enables more information about a patient’s real-life BP control (Citation1). It provides a comprehensive assessment of hypertension and better cardiovascular risk estimation (Citation2). It has a stronger association with end-organ damage and has powerful prognostic evidence (Citation3,Citation4).
The BP measures are lower at night and the mean nocturnal BP value decreases by more than 10% compared to daytime measurements. This decrease is named as dipping pattern (Citation5). Nondipping pattern is named when BP decrease is lower than 10% in sleep. The necessity of classification of BP as dipping and nondipping comes from the significant difference in cardiovascular morbidity and mortality between the two groups. The nondipping status has been shown as a stronger predictor of cardiovascular outcomes compared to daytime BP values (Citation6–8). Nocturnal BP measures have been shown to be associated with total, cardiovascular and non-cardiovascular mortality while daytime measures were associated with non-cardiovascular mortality (Citation9). Studies have shown that shifting one of the antihypertensive agents to the nighttime except diuretics has resulted in a significant decrease in 24-h mean BP values and restoration of dipping physiology with significant reductions in all causes of death, total cardiovascular events and cardiovascular deaths (Citation10–12).
Fixed dose triple antihypertensive drugs including a renin angiotensin system blocker, a diuretic and a calcium channel blocker in a single pill improve adherence to antihypertensive treatment by simplification of treatment regimen and reducing BP more effectively. Although their BP-lowering effect can be predicted by using appropriate doses described in previous randomized trials, evening intake of these drugs for a positive effect on the dipping pattern is not a known recommendation due to the diuretic component of these drugs (Citation13).
The aim of our study was to investigate the effect of timing of fixed-dose triple antihypertensive combinations, one component of which was a diuretic, on the dipping pattern in hypertensive patients.
Method
The investigation conformed to the principles outlined in the Declaration of Helsinki. The study was approved by the local ethics committee (approval number: 2018–05/2). All participants gave written informed consent.
Patients were selected among cases referred to the cardiology outpatient clinic for evaluation of hypertension from April 2018 to December 2018. After the exclusion of the patients with grade I hypertension, secondary hypertension, significant valvular heart disease, neuromuscular disorders, peripheral arterial disease, symptomatic arrhythmia, hepatic or renal failure, active connective tissue diseases that can affect BP measurements and also the circadian rhythm; 116 consecutive patients with grade II hypertension were included in the study. Grade-II hypertension was defined as systolic BP ≥160 mmHg and/or diastolic BP ≥100 mmHg according to JNC VIII (Citation14). All patients underwent baseline physical examination and were evaluated for presence of comorbidities such as hyperlipidemia, diabetes mellitus, coronary artery disease and smoking. Triple antihypertensive treatment was started within one week after diagnosis. The patients were randomized into four groups. Group 1 and Group 2 patients were given angiotensin-converting enzyme inhibitor (ACEI) based triple antihypertensive pills (perindopril 5 mg + amlodipine 5 mg + indapamide 1.25 mg) to be taken in the morning or the evening, respectively while Group 3 and Group 4 patients were given angiotensin-receptor blocker (ARB) based triple antihypertensive pills (valsartan 160 mg + amlodipine 5 mg + hydrochlorothiazide 12.5 mg) to be taken in the morning or the evening, respectively.
Ambulatory BP monitoring was performed 1 month after the initiation of the antihypertensive treatment. Ambulatory BP monitoring was performed using a noninvasive recording system (MOBIL-O-Graph New Generation, Vers.20, Ambulatory Blood Pressure Monitor, Stolberg/Germany). The device was programmed to measure BP every 30 min during the daytime (06.00–22.00) and every 60 min at nighttime (22.00–06.00) during the 24 h. The cuff was placed around the non-dominant arms of the patients and the patients were instructed not to move their arms during measurements. Sleep and awake periods were assessed based on the self-information of the patients. Patients were questioned about their sleep quality and 24-h BP assessments were repeated if necessary.
Mean daily, daytime and nocturnal systolic and diastolic BP values of the patients were noted. Nocturnal systolic BP dipping was calculated as (%) 100× [1 – (sleep systolic BP/awake systolic BP)]. Patients with decreased nocturnal BP ≥ 10% were defined as dippers while patients with less than 10% decrease were defined as nondippers (Citation5). Two additional abnormal BP patterns, namely reverse dipping (nocturnal rise in nighttime BP) and extreme dipping (nocturnal fall in nighttime BP of greater than 20%) were included in the nondipper group due to the small number of patients. BP load was calculated as a percentage of ambulatory systolic and diastolic BP values ≥140/90 mmHg in the daytime (awake) and ≥120/80 mmHg in nocturnal (sleep) measurements.
Statistical analysis
Statistical analyses were performed by statistical software (SPSS 11.0 for windows, Chicago, IL). Continuous variables were checked for normal distribution by the Kolmogorov–Smirnov test and were expressed as mean ± standard deviation. Student’s t-test and ANOVA were used to compare the normally distributed continuous parameters while Mann–Whitney U test and Kruskal–Wallis tests were used to compare the continuous variables not displaying normal distribution. Categorical variables were expressed in numbers or percentages and were compared with Pearson’s chi-square test. Logistic regression analysis was performed to determine the independent predictors of nondipping BP patterns. Statistical significance was accepted as a P value less than 0.05.
Results
One hundred and sixteen consecutive patients diagnosed with Grade−2 hypertension were included in the study. The mean age of the patients was 62.7 ± 10.7 years and 38 patients (32.8%) were male. The baseline characteristics of the patients according to the timing of fixed-dose triple antihypertensive drugs are shown in . There were not any significant differences in clinical characteristics among groups.
Table 1. The general characteristics of the patients according to timing of antihypertensive drug.
The ambulatory BP monitoring parameters of the patients are shown in . The average systolic and diastolic BP of our study population were 124.3 ± 14.4 mmHg and 75.5 ± 9.9 mmHg, respectively. All patients in each group had good BP control. The BP load of all patients was <40%, with a mean systolic BP load of 30.9 ± 28.6% and a mean diastolic BP load of 23.9 ± 24.2%. There were no significant differences in BP loads among groups.
Table 2. Ambulatory blood pressure monitoring parameters of the patients.
Dipping pattern in systolic BP was observed significantly less in Group 3 patients taking ARB in the morning 3 patients (10.3%) compared to 12 patients (41.4%) in each group, (P = .025). Similarly, dipping pattern in diastolic BP was observed significantly less in Group 3 patients [4 patients (13.8%)] compared to other groups [13 patients in Group 1 (44.8%),15 patients in Group 2 (51.7%) and 15 patients in Group 4 (51.7%), P = .008].
The characteristics of the patients according to dipping status are shown in . There were not any significant differences in the characteristics of the patients according to dipping status; except the nighttime average systolic and diastolic BP. Logistic regression analysis revealed that nondipping pattern was significantly associated with taking ARB in the morning, even when adjusted by age, sex and other comorbidities ().
Table 3. The characteristics of the patients according to dipping status.
Table 4. Logistic regression analysis to predict the independent predictors of nondipping status.
Discussion
Our study showed that there were not any significant differences in systolic and diastolic BP values and loads among groups using fixed-dose triple antihypertensive drugs at different times of the day. While all the groups had well-controlled BP; our study suggested that ARB-based combination drugs provided dipping physiology better when they were taken in the evening. On the other hand, there was no difference in the maintenance of circadian rhythm between taking ACEI-based triple combination drugs in the morning and the evening.
Grade−2 hypertension often requires antihypertensive combination treatment according to recent guidelines (Citation4). Starting antihypertensive therapy with a drug combination is associated with a greater reduction of BP, an earlier achievement of therapeutic goals, and a higher proportion of patients achieving targets with favorable implications on cardiovascular events. However, one-fourth to one-third of hypertensive patients fail to achieve BP control even with dual-combination therapies, requiring three or more antihypertensive agents (Citation15). In our study, patients in all groups had good BP control under triple antihypertensive treatment regimens. Similar to our study, the 24-h antihypertensive efficacy of a triple fixed-dose combination of an ACEI or ARB with a diuretic and a calcium channel blocker has been shown in several studies (Citation16,Citation17). Potent antihypertensive efficacy might be attributed to increasing adherence to therapy with the formation of a single-pill concept.
In normal circadian rhythm, BP and heart rate are at the lowest level in the night, starting to rise in the early morning and reach peak values in the late morning (Citation18). In people who meet the definition of the dipper, the course of BP fluctuation shows the same pattern as the normal circadian rhythm. In the nondipper group, systolic and diastolic BP are monotonous during the day but reach the highest level at night unexpectedly with the lowest BP levels observed in the daytime (Citation19). In addition to good BP control, restoration of circadian rhythm has a positive effect on cardiovascular adverse events (Citation20). Before using single pill triple antihypertensive combinations, dipping physiology has been tried to be arranged by regulating the timing of the drugs. The MAPEC study has explored the impact of a bedtime versus morning antihypertensive treatment regimen on cardiovascular morbidity and mortality risk reduction (Citation12). In this prospective study, a total of 2156 hypertensive patients were randomized to take all their drugs either after awakening or one or more drugs taken at bedtime. After a follow-up for 5 years; it was shown that bedtime chronotherapy with ≥1 BP-lowering medications had more effective BP control and restoration of dipping physiology while significantly reducing cardiovascular morbidity and mortality, compared to conventional treatment with all medications taken in the morning. Similarly, Zhao et al. (Citation11) have shown that bedtime dosing of antihypertensive medication had better BP control compared to morning administration. A recent meta-analysis has revealed that the evening treatment regimen including ACEI/ARB and calcium channel blockers as monotherapy or combination therapy reduces the morning BP surge without any side effects (Citation21). In the HYGIA Project, which is the largest prospective randomized trial to date about evening regimen, administration of ≥1 antihypertensive therapy in the evening has resulted in better BP control, effective nocturnal BP reduction, better lipid profile, and improved renal function. The most important result of this study was the demonstration of a 45% reduction in cardiovascular outcomes at 6-year follow-up by chronotherapy (Citation22). In all these studies, the benefit of taking an ACEI or an ARB in the evening was attributed to the activation of the renin-angiotensin-aldosterone system in parallel with circadian rhythm. The lowest level of renin is seen at 4 pm. It starts to increase during night reaching its highest level around 8 am and then decreases. In our study, we used perindopril as ACEI and valsartan as ARB. A relatively shorter half-life of valsartan compared to perindopril might explain the efficacy of valsartan better when taken in the evening while the efficacy of perindopril was similar between morning and evening administration.
Study limitations
The major limitations of our study were the small sample size and being a single-center study. Ambulatory BP monitoring was not performed before the initiation of antihypertensive treatment which limited to determine the initial dipping/nondipping status of the patients and the effect of each chronotherapy of the fixed-dose triple antihypertensive pill on initial dipping/nondipping status. One patient with reverse dipping and one patient with extreme dipping were included in the nondipper group due to the small number of patients. However, the expected risk of these patients might not be same compared to patients with nondipping status. The combination drugs used in our study included perindopril and indapamide as ACEI and diuretic and valsartan and hydrochlorothiazide as ARB and diuretic. Therefore, not only the timing of taking medication but also the differences in the class of antihypertensive drugs such as ACEI versus ARB and in the type of diuretics might affect the results of this study. Besides, our results might not be extrapolated for other combination drugs with a different ACEI or ARB or diuretics. Further studies are still needed to prove the reliability of the subgroup analysis due to the small number of patients.
Conclusion
Our results suggest that ACEI or ARB-based fixed-dose triple antihypertensive drugs have effective BP control in patients with grade 2 hypertension. While taking ACEI-based fixed dose triple antihypertensive drug combination at any time within a day may have the same effect on circadian rhythm, ARB-based triple combination drugs may provide dipping physiology when taken in the evening. Thus, it may be recommended to take triple-drug combinations containing ARB with bedtime chronotherapy to restore circadian rhythm, which is known to have an important role in cardiovascular outcomes.
Disclosure statement
No potential conflict of interest was reported by the authors.
Data availability statement
The data that support the findings of this study are available from the corresponding author, [BO], upon reasonable request.
Additional information
Funding
References
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