Abstract
Background
A consensus regarding the optimal time to administer anti-hypertensive medications has not been reached. Possible differential effects of different anti-hypertensive drugs on the circadian pattern of blood pressure (BP) and differential responses of individual patients receiving the same treatment at different times of the day may partly account for the controversy.
Methods
Ambulatory blood pressure monitoring (ABPM) data available at 30-min intervals for 7 days from previous studies are reanalyzed to compare the effect of five drugs (amlodipine, atenolol, captopril retard, long-acting carteolol, and nilvadipine) taken 1.5 h after awakening or twice a day on the 24-h profile of BP from 7 to 13 conventionally diagnosed patients per treatment group. Similar data from 30 patients receiving losartan/hydrochlorothiazide for at least one month at each of six different times in relation to their time of awakening serve to compare the effect of treatment time in different patients.
Results
Some but not all drugs affected the 24-h amplitude and/or phase of BP or the contribution of the 12-h harmonic term to modify the circadian waveform of BP. While evening dosing increased the 24-h amplitude of BP in some patients, other patients achieved such a desired effect with morning dosing.
Conclusion
Personalized optimization of treatment timing to best match a healthy circadian BP pattern is recommended, guided by chronobiological analyses of ABPM data collected over several days in view of the large day-to-day variability in all features of the 24-h BP rhythm.
Keywords: Blood pressure, Chronotherapy, Circadian, Personalized treatment, Optimization, 7-day/24-h Ambulatory monitoring
Highlights
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We show how antihypertensive drugs with different mechanisms of action change patients' circadian pattern of blood pressure
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We show how different patients respond differently to the same dose of the same drug taken at different times of day
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Accordingly, we advocate that chronotherapy of blood pressure be personalized, guided by chronobiological monitoring
1. Introduction
No consensus emerged from a 2023 meta-analysis of 72 randomized clinical trials investigating optimal morning versus evening dosing time for antihypertensive medications [1]. A large study in the UK conducted on the general population of hypertensive patients found no difference between the two treatment times in terms of major cardiovascular outcomes [2]. A prospective cohort sub-study, which considered the patients’ chronotype in addition to treatment timing, found that later chronotype was associated with an increased risk of hospitalization for non-fatal myocardial infarction when treated in the morning but with a reduced risk when treated in the evening [3]. The authors concluded that timing drug administration to the endogenous circadian rhythm might enhance treatment efficacy. The merits of a personalized approach to treatment are illustrated herein from a methodological perspective.
Chronotype, a person's natural tendency to sleep and be active at certain times of the day, is a behavioral expression of the body's circadian rhythm. It refers to the endogenous circadian clock. Having one's circadian system aligned to the natural environment is generally thought to be beneficial for health. It may be particularly true in the case of blood pressure (BP), which is a complex genetic trait. In clinical health, BP usually assumes its lowest values during nighttime rest, and increases rapidly upon awakening to maintain higher values during the awake daytime. Ambulatory BP monitoring (ABPM) of clinically healthy men and women of different ages served to derive chronobiological reference values that account for the circadian variation in BP. They all show a similar pattern, albeit with changes in 24-h amplitude and phase and in the extent of the post-prandial dip in early afternoon as a function of sex and age [4]. Not everyone's BP fits the same pattern, however. In addition to results from larger studies, we systematically provided elsewhere [5] detailed descriptions of different abnormal presentations of the circadian BP rhythm in a number of case reports. They illustrate that different patients can present with very different 24-h profiles of BP at the time of diagnosis. Diabetes [6,7] and obesity [8] have been associated with a weakened circadian variation in BP, sometimes also shifted in phase. A greatly reduced circadian amplitude of BP also characterizes patients with malignant hypertension [9], while some patients with chronic kidney disease have a reversed circadian rhythm in BP that peaks during nightly sleep [10]. Overall, patients with a weakened circadian BP variation or with elevated nocturnal BP values are at increased cardiovascular disease risk [[11], [12], [13]]. On the other hand, even otherwise normotensive individuals with too large a circadian variation in BP are also at increased risk of cardiovascular disease, cerebral ischemic events and nephropathy in particular [14,15]. An exaggerated circadian BP variation tends to characterize patients with pre-hypertension (or borderline hypertension) [[16], [17], [18]]. The 12-h component, which modifies the circadian waveform, also plays a role. When the phase of the 12-h component is about the same as that of the 24-h component, BP assumes similar values during the awake daytime when it more or less plateaus. When the phase difference between these two components differs too much, however, the circadian pattern of BP presents with a morning or evening surge [19]. A morning BP surge has been associated with an increased cardiovascular disease risk [20].
Lowering BP is important in the prevention of cardiovascular disease [21]. The need to restore a healthy circadian pattern of BP has now also been recognized [14,15,22]. Most studies investigating the efficacy of anti-hypertensive drugs rely on single BP measurements taken on a large number of patients to determine the extent of BP lowering achieved. Some investigations using 24-h ABPM also assess the extent of BP lowering separately during the awake (day) and asleep (night) spans, together with a measure of nighttime dipping [11,12]. Few, however, estimate circadian rhythm parameters and test the effect of treatment on the 24-h amplitude and phase in addition to the MESOR (rhythm-adjusted mean value). Our reanalysis of data from two previous studies examines how different anti-hypertensive drugs taken 1.5 h after awakening or twice a day may differently affect the patients’ 24-h BP rhythm. We also determine the response of different patients to the same drug combination administered at each of six different times of day in relation to their time of awakening to see whether it is feasible to recommend a common optimal treatment time for all patients.
2. Materials and methods
This investigation consists of a re-analysis of data already available from two previously published studies on similar populations of patients with moderate hypertension [23,24]. In the absence of treatment, ABPM results averaged (SBP/DBP MESOR, mean ± SD) 149.3 ± 9.0/90.0 ± 6.1 mmHg in Study 1 and 146.5 ± 12.2/90.5 ± 12.1 mmHg in Study 2 (p > 0.35).
Models consisting of cosine curves with periods of 24 (or 24 and 12) hours were fitted by cosinor [25,26] to yield estimates of the MESOR (M, rhythm-adjusted mean), amplitude (A) and acrophase (ϕ, phase of maximum of fitted component in relation to local midnight used as reference time). Deviation of estimated M, 24-h A and ϕ from chronobiological norms [4,5] served to identify MESOR-hypertension, CHAT (circadian hyper-amplitude-tension, when the amplitude is too large), and ecphasia (when the acrophase falls outside the 90% prediction limits of clinically healthy peers matched by gender and age). Characteristics were compared by parameter tests on treatment versus before treatment (Study 1) and among treatment times (Study 2). The comparison was performed by population-mean cosinor considering the response of individual patients, and by testing the equality of parameters of the 24-h cosine model fitted to the profiles averaged across patients.
2.1. Study 1
Five different anti-hypertensive drugs were tested on small groups of conventionally diagnosed hypertensive patients [23]. MESOR-hypertension was confirmed by ABPM prior to treatment. Drugs were amlodipine (5 mg, 1.5 h after awakening, 7 patients), atenolol (50 mg, 1.5 h after awakening, 8 patients), captopril retard (37.5 mg, 1.5 and 13.5 h after awakening, 13 patients), long-acting carteolol (15 mg, 1.5 h after awakening, 11 patients), and nilvadipine (4 mg, 1.5 and 13.5 h after awakening, 8 patients). The 47 patients (31 women and 16 men) were 28–68 years of age (mean ± SD: 52.1 ± 10.4). Hypertension was diagnosed conventionally according to guidelines used at the time (on 3 occasions, a systolic BP > 160 and/or a diastolic BP > 95 mmHg or both).
Systolic (S) and diastolic (D) BP were measured automatically at 30-min intervals around the clock for about 7 days before starting treatment and again after at least one month on treatment. The ABPM used in this study was the ABPM-630 from Colin Electronics (Komaki, Japan).
SBP and DBP data of each weeklong record were stacked over an idealized 24-h day and averaged at each of the 48 time points across all days (30 min apart). In order to minimize inter-individual differences, average 24-h profiles of each patient obtained before treatment were normalized by expressing the data as percentages of their 24-h mean value. The same mean value was used to normalize individual average profiles obtained during treatment. Mean individual 24-h profiles of SBP and DBP (in original units and after normalization) were further averaged across patients, before and during treatment with each separate anti-hypertensive medication. Graphs of the results visualize the effect of each drug. Paired t tests at each of the 48 time points assess time windows during the 24-h day when the effect of treatment was statistically significant.
2.2. Study 2
The effect of losartan/hydrochlorothiazide (L/H) on the circadian variation of BP was tested on 30 hypertensive patients (17 women and 13 men) who were each treated for at least one month at each of six different times in relation to their time of awakening [24]. They ranged in age from 38 to 86 years (mean ± SD: 64.4 ± 17.6). Eligible patients in this study had not reached the BP goals as recommended by the Japanese Society of Hypertension despite three or more months of antihypertensive agents or non-pharmacologic intervention, and had conventional measurements of SBP >140 mmHg and/or DBP >90 mmHg.
Each patient provided a 7-day/24-h ABPM record, first before starting treatment with L/H, and thereafter after at least one month on L/H taken at a specified time, that time changing after about one month to be either the time of awakening, or 3, 6, 9, 12, or 15 h after awakening. These treatment times were chosen to cover 6 treatment times spread equally between the time of awakening and bedtime. Measurements were automatically taken around the clock at 30-min intervals with the TM-2430 monitor from A&D (Tokyo, Japan).
3. Results
3.1. Study 1
[Fig. 1] compares the 24-h variation in SBP and DBP on treatment versus before treatment. Differences are apparent to the naked eye. For instance, larger overall decreases in BP are achieved with amlodipine and atenolol than with captopril retard. Whereas BP is reduced more or less equally throughout the 24 h with amlodipine and nilvadipine, long-acting carteolol and atenolol lower BP mostly during the awake daytime.
Fig. 1.
Average response of systolic (left) and diastolic (right) blood pressure of 7–13 hypertensive patients to one of five different anti-hypertensive agents. In addition to different extents of blood pressure lowering effect, atenolol and long-acting carteolol are also associated with a reduction of the 24-h amplitude of blood pressure, and long-acting carteolol is associated with a 1-h advance in the 24-h acrophase of blood pressure. Considering how the 12-h component modifies the circadian waveform of blood pressure, predicted maxima shifted considerably from morning to evening (atenolol) or from evening to morning (long-acting carteolol).
Overall, SBP/DBP decreased from 148.3/89.2 to 132.7/80.4 mmHg on amlodipine. Individually, SBP decreased from 6.5 to 21.6 mmHg and DBP from 3.8 to 14.9 mmHg. BP lowering was statistically significant for 6 of the 7 patients. A consistently significant decrease of 12.2–25.4 mmHg occurred during most of the awake span (between 07:00 and 20:00). The 2-component model consisting of cosine curves with periods of 24 and 12 h was statistically significant for both SBP and DBP before and during treatment (p < 0.001) by cosinor applied to the average 24-h BP profiles, [Table 1]. Parameter tests applied to the normalized data found only the decrease in BP MESOR to be significant (p < 0.001) by population-mean cosinor, [Table 2]. By single cosinor applied to the average 24-h BP profiles, a reduction in the 24-h amplitude was also documented, whether considering the data expressed in original units or after normalization, [Table 3].
Table 1.
Two-component model fitted to average 24-h BP profiles before and during anti-hypertensive treatment.
| 24-h component |
12-h component |
Composite model |
|||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Rx | M | PR | P | A | ϕ | PR | P | A | ϕ | PR | P | Mag | Orthoϕ (°) | Bathyϕ (°) | Oϕ (hh:mm) | Bϕ (hh:mm) | |
| Amlodipine (5 mg, AW+1.5 h, k = 7) (calcium channel blocker) | |||||||||||||||||
| SBP | Before | 148.317 | 81.0 | <0.001 | 11.986 | −223.0 | 9.0 | <0.001 | 3.974 | −264.0 | 90.0 | <0.001 | 12.290 | −264.0 | −42.0 | 17:36 | 02:48 |
| During | 132.674 | 71.0 | <0.001 | 8.824 | −228.0 | 15.0 | <0.001 | 4.066 | −257.0 | 86.0 | <0.001 | 10.254 | −280.0 | −42.0 | 18:40 | 02:48 | |
| DBP |
Before | 89.243 | 80.0 | <0.001 | 7.591 | −222.0 | 10.0 | <0.001 | 2.693 | −254.0 | 90.0 | <0.001 | 8.044 | −267.0 | −39.0 | 17:48 | 02:36 |
| During | 80.379 | 68.0 | <0.001 | 5.849 | −225.0 | 20.0 | <0.001 | 3.191 | −256.0 | 88.0 | <0.001 | 7.078 | −283.0 | −40.0 | 18:52 | 02:40 | |
| Atenolol (50 mg, AW+1.5 h, k = 8) (β-blocker) | |||||||||||||||||
| SBP | Before | 146.440 | 80.0 | <0.001 | 12.350 | −218.0 | 11.0 | <0.001 | 4.648 | −275.0 | 92.0 | <0.001 | 13.563 | −173.0 | −44.0 | 11:32 | 02:56 |
| During | 131.411 | 45.0 | <0.001 | 4.864 | −230.0 | 34.0 | <0.001 | 4.257 | −249.0 | 79.0 | <0.001 | 7.584 | −290.0 | −38.0 | 19:20 | 02:32 | |
| DBP |
Before | 88.859 | 79.0 | <0.001 | 8.390 | −215.0 | 14.0 | <0.001 | 3.474 | −278.0 | 93.0 | <0.001 | 9.643 | −169.0 | −44.0 | 11:16 | 02:56 |
| During | 78.592 | 40.0 | <0.001 | 3.336 | −228.0 | 43.0 | <0.001 | 3.442 | −250.0 | 83.0 | <0.001 | 5.633 | −292.0 | −37.0 | 19:28 | 02:28 | |
| Captopril retard (37.5 mg, AW+1.5 & AW+13.5 h, k = 13) (angiotensin-converting enzyme inhibitor) | |||||||||||||||||
| SBP | Before | 149.001 | 75.0 | <0.001 | 10.905 | −233.0 | 17.0 | <0.001 | 5.158 | −282.0 | 92.0 | <0.001 | 12.223 | −290.0 | −52.0 | 19:20 | 03:28 |
| During | 140.549 | 73.0 | <0.001 | 11.133 | −240.0 | 22.0 | <0.001 | 6.176 | −260.0 | 95.0 | <0.001 | 14.337 | −289.0 | −46.0 | 19:16 | 03:04 | |
| DBP |
Before | 88.376 | 73.0 | <0.001 | 7.298 | −230.0 | 19.0 | <0.001 | 3.693 | −283.0 | 91.0 | <0.001 | 8.308 | −171.0 | −51.0 | 11:24 | 03:24 |
| During | 83.303 | 69.0 | <0.001 | 7.042 | −237.0 | 26.0 | <0.001 | 4.288 | −258.0 | 95.0 | <0.001 | 9.347 | −289.0 | −44.0 | 19:16 | 02:56 | |
| Long-acting carteolol (15 mg, AW+1.5 h, k = 11) (β-blocker) | |||||||||||||||||
| SBP | Before | 150.181 | 79.0 | <0.001 | 13.535 | −220.0 | 17.0 | <0.001 | 6.206 | −253.0 | 96.0 | <0.001 | 15.142 | −275.0 | −37.0 | 18:20 | 02:28 |
| During | 141.207 | 74.0 | <0.001 | 8.785 | −208.0 | 15.0 | <0.001 | 4.000 | −241.0 | 89.0 | <0.001 | 9.758 | −153.0 | −30.0 | 10:12 | 02:00 | |
| DBP |
Before | 97.214 | 79.0 | <0.001 | 9.852 | −219.0 | 17.0 | <0.001 | 4.616 | −253.0 | 96.0 | <0.001 | 11.065 | −275.0 | −37.0 | 18:20 | 02:28 |
| During | 90.548 | 72.0 | <0.001 | 6.454 | −206.0 | 16.0 | <0.001 | 3.036 | −250.0 | 88.0 | <0.001 | 7.502 | −154.0 | −32.0 | 10:16 | 02:08 | |
| Nilvadipine (4 mg, AW+1.5 & AW+13.5 h k = 8) (dihydropyridine calcium channel blocker) | |||||||||||||||||
| SBP | Before | 152.129 | 68.0 | <0.001 | 9.420 | −225.0 | 25.0 | <0.001 | 5.720 | −257.0 | 92.0 | <0.001 | 11.868 | −286.0 | −40.0 | 19:04 | 02:40 |
| During | 140.768 | 65.0 | <0.001 | 8.656 | −220.0 | 26.0 | <0.001 | 5.529 | −245.0 | 91.0 | <0.001 | 11.203 | −281.0 | −35.0 | 18:44 | 02:20 | |
| DBP | Before | 93.406 | 67.0 | <0.001 | 6.554 | −218.0 | 26.0 | <0.001 | 4.099 | −256.0 | 93.0 | <0.001 | 8.038 | −151.0 | −38.0 | 10:04 | 02:32 |
| During | 86.234 | 64.0 | <0.001 | 5.908 | −219.0 | 26.0 | <0.001 | 3.741 | −244.0 | 90.0 | <0.001 | 7.599 | −280.0 | −34.0 | 18:40 | 02:16 | |
Abbreviations: SBP: Systolic Blood Pressure (mmHg); DBP: Diastolic Blood Pressure (mmHg); Rx: Treatment; M: MESOR (rhythm-adjusted mean); PR: Percentage Rhythm (proportion of overall variance accounted for by fitted component or model, %); P: P-value from zero-amplitude (no-rhythm) test; A: amplitude; ϕ: acrophase (phase of maximum in relation to local midnight used as reference time); Mag: magnitude (extent of predictable change within a cycle); Orthoϕ: orthophase (phase of maximum assumed by fitted model); Bathyϕ: bathyphase (phase of minimum assumed by fitted model). Phases are expressed in (negative) degrees, with 360°≡period length (24 or 12 h), and 0° = local midnight. Orthophases and bathyphases are also shown in hh:mm.
Table 2.
Comparison of population rhythm characteristics of blood pressure during versus before treatment.
| Rx | P | M | SE | A | SE | ϕ (°) | (95% | CI) | ϕ (hh:mm) | (95% | CI) | (A, ϕ) | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Amlodipine (5 mg, AW+1.5 h, k = 7) (calcium channel blocker) | |||||||||||||
| SBP | Before | 0.008 | 100.00 | 0.00 | 8.10 | 4.51 | −223.0 | −186.0 | −240.0 | 14:52 | 12:24 | 16:00 | |
| During | 0.013 | 89.47 | 3.48 | 5.89 | 4.19 | −229.0 | −203.0 | −292.0 | 15:16 | 13:32 | 19:28 | ||
| F | 54.828 | 0.729 | 0.102 | 0.355 | |||||||||
| P | <0.001 | 0.410 | 0.755 | 0.705 | |||||||||
| DBP |
Before | 0.025 | 100.00 | 0.00 | 8.61 | 5.84 | −222.0 | −177.0 | −241.0 | 14:48 | 11:48 | 16:04 | |
| During | 0.030 | 90.13 | 3.53 | 6.49 | 4.94 | −225.0 | −200.0 | −287.0 | 15:00 | 13:20 | 19:08 | ||
| F | 46.801 | 0.449 | 0.032 | 0.219 | |||||||||
| P | <0.001 | 0.516 | 0.861 | 0.805 | |||||||||
| Atenolol (50 mg, AW+1.5 h, k = 8) (β-blocker) | |||||||||||||
| SBP | Before | 0.015 | 100.00 | 0.00 | 8.75 | 5.29 | −218.0 | −204.0 | −247.0 | 14:32 | 13:36 | 16:28 | |
| During | 0.151 | 89.76 | 6.50 | 3.43 | 3.48 | −230.0 | – | – | 15:20 | – | – | ||
| F | 13.882 | 4.131 | 0.389 | 1.825 | |||||||||
| P | 0.002 | 0.062 | 0.543 | 0.181 | |||||||||
| DBP |
Before | 0.019 | 100.00 | 0.00 | 9.80 | 5.65 | −215.0 | −202.0 | −235.0 | 14:20 | 13:28 | 15:40 | |
| During | 0.064 | 88.52 | 6.66 | 3.82 | 2.95 | −227.0 | – | – | 15:08 | – | – | ||
| F | 16.658 | 5.086 | 0.566 | 2.237 | |||||||||
| P | 0.001 | 0.041 | 0.465 | 0.124 | |||||||||
| Captopril retard (37.5 mg, AW+1.5 & AW+13.5 h, k = 13) (angiotensin-converting enzyme inhibitor) | |||||||||||||
| SBP | Before | <0.001 | 100.00 | 0.00 | 7.39 | 2.72 | −234.0 | −217.0 | −249.0 | 15:36 | 14:28 | 16:36 | |
| During | <0.001 | 94.50 | 3.46 | 7.51 | 2.09 | −239.0 | −229.0 | −252.0 | 15:56 | 15:16 | 16:48 | ||
| F | 12.043 | 0.006 | 0.476 | 0.231 | |||||||||
| P | 0.002 | 0.940 | 0.497 | 0.795 | |||||||||
| DBP |
Before | 0.001 | 100.00 | 0.00 | 8.42 | 3.20 | −230.0 | −214.0 | −244.0 | 15:20 | 14:16 | 16:16 | |
| During | <0.001 | 94.47 | 3.42 | 8.09 | 2.39 | −237.0 | −226.0 | −249.0 | 15:48 | 15:04 | 16:36 | ||
| F | 12.404 | 0.032 | 0.583 | 0.293 | |||||||||
| P | 0.002 | 0.860 | 0.453 | 0.747 | |||||||||
| Long-acting carteolol (15 mg, AW+1.5 h, k = 11) (β-blocker) | |||||||||||||
| SBP | Before | <0.001 | 100.00 | 0.00 | 9.19 | 3.19 | −220.0 | −207.0 | −235.0 | 14:40 | 13:48 | 15:40 | |
| During | <0.001 | 94.05 | 3.80 | 5.88 | 1.90 | −208.0 | −194.0 | −227.0 | 13:52 | 12:56 | 15:08 | ||
| F | 12.218 | 3.995 | 1.276 | 3.296 | |||||||||
| P | 0.002 | 0.059 | 0.272 | 0.048 | |||||||||
| DBP |
Before | <0.001 | 100.00 | 0.00 | 10.43 | 3.52 | −217.0 | −206.0 | −231.0 | 14:28 | 13:44 | 15:24 | |
| During | <0.001 | 93.34 | 4.31 | 6.80 | 2.13 | −204.0 | −191.0 | −221.0 | 13:36 | 12:44 | 14:44 | ||
| F | 11.825 | 3.880 | 2.291 | 3.858 | |||||||||
| P | 0.003 | 0.063 | 0.146 | 0.030 | |||||||||
| Nilvadipine (4 mg, AW+1.5 & AW+13.5 h k = 8) (dihydropyridine calcium channel blocker) | |||||||||||||
| SBP | Before | 0.022 | 100.00 | 0.00 | 6.26 | 3.56 | −225.0 | −200.0 | −245.0 | 15:00 | 13:20 | 16:20 | |
| During | 0.010 | 92.62 | 5.25 | 5.78 | 2.73 | −220.0 | −207.0 | −231.0 | 14:40 | 13:48 | 15:24 | ||
| F | 11.056 | 0.064 | 0.295 | 0.148 | |||||||||
| P | 0.005 | 0.805 | 0.596 | 0.864 | |||||||||
| DBP | Before | 0.016 | 100.00 | 0.00 | 7.03 | 3.94 | −218.0 | −191.0 | −234.0 | 14:32 | 12:44 | 15:36 | |
| During | 0.011 | 92.37 | 5.07 | 6.36 | 3.06 | −219.0 | −203.0 | −235.0 | 14:36 | 13:32 | 15:40 | ||
| F | 12.705 | 0.102 | 0.016 | 0.069 | |||||||||
| P | 0.003 | 0.754 | 0.903 | 0.934 | |||||||||
Abbreviations: SBP & DBP: Systolic & Diastolic Blood Pressure (% of 24-h mean before treatment); Rx: Treatment; P: P-value from zero-amplitude (no-rhythm) test; M: MESOR (rhythm-adjusted mean); A: 24-h amplitude; ϕ: 24-h acrophase (expressed in negative degrees, with 360°≡24 h (hence 15°≡1 h); 0° = local midnight); SE: Standard Error; F & P are results of tests of equality of M, A, ϕ, and (A, ϕ) between profiles during versus before treatment.
Note decrease in 24-h amplitude with β-blockers, documented by population-mean cosinor with borderline statistical significance despite small sample sizes.
Table 3.
Effect of treatment on average 24-h profile of blood pressure.
| BP (mmHg) |
BP (% of 24h mean before Rx) |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Rx | M | A | ϕ (°) | ϕ (hh:mm) | (A, ϕ) | M | A | ϕ (°) | ϕ (hh:mm) | (A, ϕ) | |
| Amlodipine (5 mg, AW+1.5 h, k = 7) (calcium channel blocker) | |||||||||||
| SBP | Before | 148.32 | 11.99 | −223.0 | 14:52 | 100.00 | 8.10 | −223.0 | 14:52 | ||
| During | 132.67 | 8.82 | −228.0 | 15:12 | 89.47 | 5.89 | −229.0 | 15:16 | |||
| F | 340.889 | 6.964 | 0.925 | 3.808 | 341.660 | 7.503 | 0.647 | 4.089 | |||
| P | <0.001 | 0.010 | 0.431 | 0.026 | <0.001 | 0.007 | 0.424 | 0.020 | |||
| DBP |
Before | 89.24 | 7.59 | −222.0 | 14:48 | 100.00 | 8.60 | −222.0 | 14:48 | ||
| During | 80.38 | 5.85 | −225.0 | 15:00 | 90.13 | 6.48 | −225.0 | 15:00 | |||
| F | 230.658 | 4.453 | 0.158 | 2.310 | 227.902 | 5.267 | 0.167 | 2.721 | |||
| P | <0.001 | 0.038 | 0.692 | 0.105 | <0.001 | 0.024 | 0.684 | 0.071 | |||
| Atenolol (50 mg, AW+1.5 h, k = 8) (β-blocker) | |||||||||||
| SBP | Before | 146.44 | 12.35 | −218.0 | 14:32 | 100.00 | 9.74 | −218.0 | 14:32 | ||
| During | 131.41 | 4.86 | −230.0 | 15:20 | 89.76 | 3.43 | −230.0 | 15:20 | |||
| F | 306.527 | 38.024 | 1.400 | 19.960 | 304.140 | 40.935 | 1.412 | 21.429 | |||
| P | <0.001 | <0.001 | 0.241 | <0.001 | <0.001 | <0.001 | 0.239 | <0.001 | |||
| DBP |
Before | 88.86 | 8.39 | −215.0 | 14:20 | 100.00 | 9.79 | −215.0 | 14:20 | ||
| During | 78.59 | 3.34 | −228.0 | 15:12 | 88.52 | 3.82 | −227.0 | 15:08 | |||
| F | 270.788 | 32.803 | 1.316 | 17.330 | 265.596 | 35.947 | 1.187 | 18.828 | |||
| P | <0.001 | <0.001 | 0.256 | <0.001 | <0.001 | <0.001 | 0.280 | <0.001 | |||
| Captopril retard (37.5 mg, AW+1.5 & AW+13.5 h, k = 13) (angiotensin-converting enzyme inhibitor) | |||||||||||
| SBP | Before | 149.00 | 10.91 | −233.0 | 15:32 | 100.00 | 7.40 | −233.0 | 15:32 | ||
| During | 140.55 | 11.13 | −240.0 | 16:00 | 94.49 | 7.51 | −239.0 | 15:56 | |||
| F | 75.496 | 0.028 | 0.766 | 0.397 | 69.733 | 0.015 | 0.699 | 0.358 | |||
| P | <0.001 | 0.869 | 0.384 | 0.673 | <0.001 | 0.903 | 0.405 | 0.700 | |||
| DBP |
Before | 88.38 | 7.30 | −230.0 | 15:20 | 100.00 | 8.43 | −230.0 | 15:20 | ||
| During | 83.30 | 7.04 | −237.0 | 15:48 | 94.47 | 8.09 | −236.0 | 15:44 | |||
| F | 55.084 | 0.070 | 0.652 | 0.363 | 49.336 | 0.089 | 0.620 | 0.356 | |||
| P | <0.001 | 0.792 | 0.422 | 0.697 | <0.001 | 0.766 | 0.433 | 0.701 | |||
| Long-acting carteolol (15 mg, AW+1.5 h, k = 11) (β-blocker) | |||||||||||
| SBP | Before | 150.18 | 13.54 | −220.0 | 14:40 | 100.00 | 9.19 | −219.0 | 14:40 | ||
| During | 141.21 | 8.79 | −208.0 | 13:52 | 93.87 | 6.21 | −206.0 | 13:52 | |||
| F | 95.410 | 13.367 | 2.965 | 8.140 | 91.935 | 10.865 | 3.747 | 7.326 | |||
| P | <0.001 | 0.001 | 0.089 | 0.001 | <0.001 | 0.001 | 0.056 | 0.001 | |||
| DBP |
Before | 97.21 | 9.85 | −219.0 | 14:36 | 100.00 | 10.43 | −217.0 | 14:36 | ||
| During | 90.55 | 6.45 | −206.0 | 13:44 | 93.35 | 6.81 | −204.0 | 13:44 | |||
| F | 94.713 | 12.311 | 3.669 | 7.982 | 83.294 | 12.365 | 3.819 | 8.055 | |||
| P | <0.001 | 0.001 | 0.059 | 0.006 | <0.001 | 0.001 | 0.054 | 0.001 | |||
| Nilvadipine (4 mg, AW+1.5 & AW+13.5 h k = 8) (dihydropyridine calcium channel blocker) | |||||||||||
| SBP | Before | 152.13 | 9.42 | −225 | 15:00 | 100.00 | 6.26 | −225.0 | 15:00 | ||
| During | 140.77 | 8.66 | −220 | 15:40 | 92.62 | 5.78 | −220.0 | 15:40 | |||
| F | 139.495 | 0.315 | 0.288 | 0.302 | 137.578 | 0.283 | 0.351 | 0.317 | |||
| P | <0.001 | 0.576 | 0.593 | 0.740 | <0.001 | 0.596 | 0.555 | 0.729 | |||
| DBP | Before | 93.41 | 6.55 | −218 | 14:32 | 100.00 | 7.03 | −218.0 | 14:32 | ||
| During | 86.23 | 5.91 | −219 | 14:36 | 92.37 | 6.36 | −219.0 | 14:36 | |||
| F | 114.686 | 0.465 | 0.037 | 0.251 | 114.352 | 0.448 | 0.015 | 0.132 | |||
| P | <0.001 | 0.497 | 0.848 | 0.779 | <0.001 | 0.505 | 0.903 | 0.794 | |||
Abbreviations: SBP: Systolic Blood Pressure; DBP: Diastolic Blood Pressure; Rx: Treatment; M: MESOR (rhythm-adjusted mean); A: 24-h amplitude; ϕ: 24-h acrophase (expressed in negative degrees, with 360°≡24 h (hence 15°≡1 h) and 0° = local midnight); F & P: results of parameter tests comparing M, A, ϕ, and (A, ϕ) during versus before treatment.
In the case of atenolol, SBP/DBP decreased overall from 146.4/88.9 to 131.4/78.6 mmHg. All 8 patients responded with a statistically significant lowering of BP, which ranged from 2.9 to 30.8 mmHg (SBP) and from 1.8 to 21.7 mmHg (DBP). During the awake daytime (between 08:00 and 22:00), BP decreased significantly (except for DBP on two of the covered time points). Decreases ranged from 8.3 to 28.6 mmHg (SBP) and from 4.6 to 18.6 mmHg (DBP). The 2-component model was invariably significant for SBP and DBP before and during treatment (p < 0.001), [Table 1]. In addition to the lowering in MESOR (p < 0.001), atenolol also decreased the 24-h amplitude considerably, to the point that a 24-h rhythm did not reach statistical significance by population-mean cosinor during treatment, [Table 2]. By single cosinor, the amplitude decreased from 12.4 to 4.9 mmHg (SBP) and from 8.4 to 3.3 mmHg (DBP) (p < 0.001), [Table 3]. As a result, the 12-h component, which is not dampened on treatment, contributes to the circadian waveform of BP to a larger extent during than before treatment, thereby delaying the time of predicted maximum by 7.8 (SBP) and 8.2 (DBP) hours, [Table 1] and [Fig. 1].
SBP and DBP decreased overall from 149.0/88.4 to 140.6/83.3 mmHg on captopril retard. Only 11 of the 13 patients responded with a reduced SBP. The other 2 patients showed a slight, non-significant increase in SBP. DBP decreased significantly in 9 of the 13 patients, 1 additional patient showing a small decrease of borderline significance, while the other 3 patients had no significant change in DBP. Individual responses ranged from a 1.6-mmHg increase to a 34.0-mmHg decrease in SBP and from a 1.8-mmHg increase to a 20.9-mmHg decrease in DBP. Despite the smaller overall decrease in BP, more or less consistently significant decreases were found during part of the awake daytime (between 09:00 and 18:30), as well as during part of the nightly rest span (between 22:00 and 05:00 and between 06:00 and 07:30). Decreases during those times ranged from 4.7 to 15.8 mmHg (SBP) and from 1.8 to 10.6 mmHg (DBP). The 2-component model was invariably significant for SBP and DBP before and during treatment (p < 0.001), [Table 1]. Only a decrease in MESOR was substantiated by parameter tests (p < 0.005), [Table 2, Table 3]
Long-acting carteolol decreased SBP/DBP from 150.2/97.2 to 141.2/90.5 mmHg. Among the 11 patients, 8 responded with a significant decrease in SBP, 2 showed no difference in SBP on treatment, and 1 had a significant increase in SBP. Eight responded with a significant decrease in DBP, another 1 with a decrease in DBP of borderline statistical significance, 1 had no difference in DBP on treatment, and 1 had a significant increase in DBP. Individual responses ranged from a 7.3-mmHg increase to a 22.2-mmHg decrease in SBP and from a 7.4-mmHg increase to a 15.0-mmHg decrease in DBP. For 11 h, mostly during the awake daytime (between 12:00 and 23:00), BP was consistently significantly decreased (except for DBP on two of the covered time points). Decreases ranged from 7.6 to 18.1 mmHg (SBP) and from 5.8 to 14.2 mmHg (DBP). The 2-component model was invariably significant for SBP and DBP before and during treatment (p < 0.001), [Table 1]. In addition to a significant lowering of the MESOR (p < 0.005), long-acting carteolol also reduced the 24-h amplitude of BP. By population-mean cosinor, the decrease reached borderline statistical significance (SBP: p = 0.059; DBP: p = 0.063), [Table 2]. Considering the about 1-h advance in the 24-h acrophase on treatment (SBP: from 14:40 to 13:52; DBP: from 14:36 to 13:44), a significant difference in (A, ϕ) was documented (p < 0.05), [Table 2]. A comparison of the average 24-h BP profiles corroborated these results, showing a significant reduction in the 24-h amplitude (p ≤ 0.001) and an about 1-h advance in the 24-h acrophase of borderline statistical significance (p < 0.100), [Table 3]. Considering the contribution of the 12-h component to the circadian waveform of BP, the time of predicted maximum advanced by about 8 h on treatment, [Table 1] and [Fig. 1].
In the case of nilvadipine, SBP/DBP decreased overall from 152.1/93.4 to 140.8/86.2 mmHg. Of the 8 patients on this medication, 7 responded with a significant decrease in SBP and 1 patient with an increase in SBP of borderline statistical significance. DBP was decreased with statistical significance in 7 patients, while no difference in DBP was found for the other patient. Individual responses ranged from a 2.5-mmHg increase to a 27.6-mmHg decrease in SBP and from a 1.1-mmHg increase to an 18.0-mmHg decrease in DBP. Statistically significant decreases in BP were observed mostly throughout the 24 h (38/33 of the 48 time points in the case of SBP/DBP). Decreases ranged from 4.7 to 19.3 mmHg (SBP) and from 1.3 to 11.6 mmHg (DBP). The 2-component model was invariably significant for SBP and DBP before and during treatment (p < 0.001), [Table 1]. Nilvadipine lowered the BP MESOR without significantly altering the 24-h amplitude or acrophase, [Table 2, Table 3]
3.2. Study 2
As originally reported [24], the 2-component model statistically significantly approximated more than 95% of the records. Treatment time accounted for differences of 10.9 ± 5.2 mmHg in SBP MESOR and of 6.4 ± 3.0 mmHg in DBP MESOR. It also accounted for equally large differences of 9.2 ± 4.3 and 5.5 ± 2.7 mmHg in the 24-h amplitude of SBP and DBP, respectively. These differences affected most of the patients examined. While overall treatment timing did not make a difference in terms of the SBP MESOR or 24-h amplitude, the MESOR of DBP tended to be lower when treatment was taken daily upon awakening or 12 or 15 h after awakening, and higher when treatment was taken daily 6 h after awakening (F = 2.243, p = 0.052). On average across all 30 patients, treatment taken 6–12 h after awakening also tended to be associated with 24-h amplitudes of DBP that were 3%–10% larger than treatment at other times.
[Fig. 2] illustrates the extent to which treatment timing can affect an individual patient's 24-h profile of BP. For this 66-year old patient, the MESOR estimates of SBP/DBP were 121.1/76.3, 120.4/79.1, 126.0/79.3, 109.4/71.5, 108.9/72.1, and 114.6/75.5 mmHg when treatment was administered for at least one month either upon awakening, or 3, 6, 9, 12, or 15 h after awakening. Lowest BP MESORs were achieved when L/H was taken daily 9–12 h after awakening. The corresponding 24-h amplitude estimates of SBP/DBP were 19.7/11.6, 16.0/12.2, 21.4/9.5, 11.7/8.5, 10.3/6.2, and 10.4/7.5 mmHg, respectively. Treatment time accounted for statistically significant differences in MESOR (SBP: F = 8.990, p < 0.001; DBP: F = 6.334, p < 0.001) as well as in the 24-h amplitude (SBP: F = 7.475, p < 0.001; DBP: 3.132, p = 0.020), as assessed by one-way analysis of variance of daily estimates of 24-h parameters.
Fig. 2.
Average 24-h profiles of systolic and diastolic blood pressure of a 66-year old hypertensive man. He provided around-the-clock measurements at 30-min intervals for 7 days after taking losartan/hydrochlorothiazide for at least one month on each of six different occasions when treatment was taken daily either upon awakening (top left), 3 (top, center), 6 (top, right), 9 (bottom, left), 12 (bottom, center), or 15 (bottom, right) hours after awakening. While he used the same dose of the same treatment in each case, the average SBP achieved on treatment ranged from 108.6 to 127.1 mmHg and the average DBP ranged from 71.6 to 80.1 mmHg. Corresponding estimated 24-h amplitudes also varied greatly depending on the timing of treatment, namely from 10.6 to 24.4 (SBP) and from 7.1 to 16.0 mmHg (DBP). The timing of overall high values recurring each day varied from around 10:00 a.m. when the patient took the medication in the evening to 6–8 h later when he took the same dose of the same medication 3–12 h after awakening. Deciding on the optimal treatment time for this patient needs balancing all aspects of his 24-h variation in blood pressure.
In some patients, changing the treatment time modifies the circadian profile of BP without necessarily altering the extent of lowering of the 24-h BP average, as illustrated in [Fig. 3] for the case of a 60-year old man. The daily estimates of SBP/DBP MESORs ranged from 99.4/66.9 to 116.0/78.3 mmHg and from 102.3/65.9 to 121.3/82.8 mmHg when L/H was taken daily for about one month 3 or 12 h after awakening, respectively. Corresponding estimates of the 24-h amplitudes of SBP/DBP varied from 4.0/2.7 to 13.4/10.8 mmHg and from 13.0/11.3 to 21.3/18.3 mmHg, respectively. In the absence of a difference in MESOR between the two treatment times (p > 0.25), the 24-h amplitude was larger when treatment was administered 12 h after awakening as compared to 3 h after awakening (SBP: F = 35.008, p < 0.001; DBP: F = 19.602, p = 0.001), as assessed by one-way analysis of variance of daily estimates of 24-h parameters. The 12-h harmonic term contributed significantly to the circadian waveform, notably when treatment was taken 3 h after awakening, as shown by the fit of a 2-component model to the average 24-h profiles of SBP and DBP, [Fig. 3]. In this patient, the timing of treatment also modified the 24-h acrophase of BP greatly, which was delayed by about 7 (SBP) and 3.3 (DBP) hours, thereby changing a mild morning surge to a more pronounced evening surge in BP, [Fig. 3]. Statistically significant differences between the two treatment times were confirmed by parameter tests applied to the average 24-h profiles for both the 24-h amplitude (SBP: F = 39.674, p < 0.001; DBP: F = 30.409, p < 0.001) and the 24-h acrophase (SBP: F = 9.828, p = 0.003; DBP: F = 4.226, p = 0.045).
Fig. 3.
Average 24-h profiles of systolic and diastolic blood pressure of a 60-year old hypertensive man computed from 7-day/24-h ABPM records of measurements at 30-min intervals obtained after taking losartan/hydrochlorothiazide daily for at least one month either 3 (left) or 12 (right) hours after awakening. In the absence of a difference in MESOR, the 24-h amplitude of both SBP and DBP more than doubles when he takes losartan/hydrochlorothiazide daily later in the day, suggesting that this treatment time may be preferred for this patient.
[Fig. 4] illustrates how the presumed best treatment time (gauged here by the extent of nocturnal dip in BP) can differ from one patient to another. In the light of similar decreases in BP MESOR, a treatment associated with a larger circadian variation (a larger nighttime dip) is regarded as being more beneficial than a treatment associated with a smaller circadian variation in BP (as long as it is not excessive). Treatment in the evening (15 h after awakening) for a 62-year old woman achieved a well-defined circadian BP variation when the same treatment taken upon awakening did not ([Fig. 4], top). The opposite situation, however, characterized a 78-year old man and another 73-year old man ([Fig. 4], bottom). In the former case, the 24-h amplitude was larger when treatment was taken 15 h after awakening than when it was taken upon awakening (SBP: 16.4 versus 10.1 mmHg, F = 4.931, p = 0.046; DBP: 10.6 versus 6.2 mmHg, F = 4.828, p = 0.048). In the latter cases, the 24-h amplitude was larger when treatment was taken upon awakening than when it was taken 15 h after awakening. In the case of the 78-year old man, they were 16.7 versus 6.7 mmHg for SBP (F = 15.048, p = 0.002) and 8.7 versus 3.6 mmHg for DBP (F = 28.976, p < 0.001). BP, however, peaked during nightly rest, therefore potentially counteracting the likely protective effect of a larger 24-h amplitude. In the case of the 73-year old man, in the absence of a difference in MESOR (p > 0.4), the 24-h amplitudes associated with the two treatment times were 12.4 versus 5.2 mmHg for SBP (F = 4.507, p = 0.037) and 7.0 versus 2.4 mmHg (F = 2.810, p = 0.097) for DBP. The 12-h harmonic contributed significantly to the circadian waveform of all three patients when treated upon awakening and of the 73-year old man and the 62-year old woman when treated 15 h after awakening. In the latter case, the 12-h acrophase was delayed with evening versus morning treatment (SBP: 2.13 h, F = 5.326, p = 0.024; DBP: 2.63 h, F = 3.298, p = 0.073).
Fig. 4.
Need to personalize the optimization of treatment timing. Average 24-h profiles of systolic and diastolic blood pressure of a 62-year old hypertensive woman (top) and of a 73-year old hypertensive man (bottom) computed from 7-day/24-h ABPM records of measurements at 30-min intervals. They were treated daily with losartan/hydrochlorothiazide for at least one month either in the morning upon awakening (left) or in the evening, 15 h after awakening (right). Whereas treatment achieved a desired nocturnal blood pressure decrease with evening dosing but not with morning dosing for one patient (top), morning rather than evening dosing is the preferred treatment time for the other patient (bottom). These results illustrate the need to personalize the optimization of treatment timing. A fixed 2-component model is considered herein to fit the data for capturing the circadian variation in blood pressure. In order to characterize variations with periods shorter than 12 h (and reduce the models' lack of fit), higher-order harmonic terms need to be incorporated in the model. Their addition to the model, however, will not change the conclusion that a more pronounced circadian variation is achieved by treatment in the evening for the 62-year old woman (top), whereas treatment in the morning achieves this goal for the 78-year old man (bottom).
4. Discussion and conclusion
The demonstration herein of inter-individual responses to treatment is precisely the reason why we find it important to personalize treatment and treatment timing. Specifically, lessons learned from these re-analyses are that anti-hypertensive drugs affect the circadian variation in BP in all its characteristics, not just its mean value (as shown in [Fig. 1]), and that the presumed optimal treatment time for a given medication can differ greatly among patients (as shown in [Fig. 2, Fig. 3, Fig. 4]). While multiple factors, including the pharmacokinetics and pharmacodynamics properties of the drug(s) used, affect BP and can account for inter-individual differences in treatment effects [27], Study 2 used a longitudinal design where the same patient was monitored after each monthly course of treatment that differed only in terms of the time of its administration. Since results pertained to a given patient, factors such as genetics, sex, age, concomitant conditions and previous events remained the same, as did the dose of the anti-hypertensive agent used, and were not confounders. Monitoring patients for 7 days also reduced the influence of other factors related to daily life. Differences found in the circadian pattern of BP in a given patient thus likely reflect primarily effects of treatment timing. Noteworthy is the concordance of results obtained whether considering original or normalized data, and whether using parameter tests of circadian characteristics estimated from the entire records or an analysis of variance of MESORs and 24-h amplitudes estimated over consecutive daily spans, independently of the phase estimation and the choice of a reference time.
Anti-hypertensive treatment aims at lowering BP while also restoring a healthy circadian BP pattern with a low enough 24-h average and a normal circadian variation that is large enough but not excessive and peaks during the awake daytime with no untoward morning (or evening) surge. Achieving this goal depends, in part, on the 12-h harmonic term, which modifies the circadian pattern of BP, as illustrated herein. Timing treatment to amplify its circadian variation may in some cases lead to BP patterns thought to be associated with a larger cardiovascular risk, such as when the 24-h amplitude becomes excessive [14,15], or when BP surges in the morning [28]. Morning (or evening) BP surges depend on the 12-h component and its coupling with the 24-h rhythm [19]. Interest in the 12-h clock stems from its contribution to the rapid adaptation to a novel environment, thereby helping the restoration of a healthy time structure in the presence of circadian disruption. The biological 12-h rhythm reflects both the function of “endogenous endoplasmic reticulum (ER) stress and unfolded protein response (UPRER) cycle” and the reaction of “mitochondrial stress response pathway and unfolded protein response (UPRmt)”, which can protect cells from widespread proteome stress in both central and peripheral tissues [29]. This may be why the biological 12-h rhythm was first activated to consolidate a stronger circadian system in space [30] and why it may be activated when treating high BP and other BP disorders.
Despite the merit of clinical trials that can lead to general guidelines, the real task is treating the patient rather than the condition. Toward that goal, it is crucial that the time of treatment be optimized for each individual patient by accounting for all features of the circadian pattern of BP and recognizing that desired treatment effects on all aspects of the 24-h BP variation may not all converge to the same optimal treatment time. Conflicting decisions may exist between lowering the average BP more or more closely restoring a healthy 24-h pattern of BP. Increasing the 24-h amplitude of BP may be beneficial for a large fraction of the hypertensive population, but it can be harmful in some cases [14,15]. Of note, an excessive 24-h amplitude of BP is not equivalent to extreme dipping. The day-night (or night-day) ratio used for a classification in terms of dipping is only poorly reproducible, contrary to the higher extent of agreement of a classification relying on the 24-h characteristics of BP (and heart rate), as documented in our weeklong ABPM records. For this reason, we relied herein on model fitting rather than on dipping categories and showed data from patients who underwent 7-day/24-h ABPM. Weeklong records are useful to account for the large day-to-day variability in all circadian characteristics of BP, as observed in the different cases reviewed herein, which stems from the multiple factors in addition to medication that all influence BP on a daily basis. Such large variability in the MESOR, 24-h amplitude and acrophase of BP, and in the extent of the post-prandial dip in early afternoon observed from one day to another was documented in men and women of all ages, irrespective of whether they were normotensive or hypertensive [31]. It is particularly important to monitor BP over several days for older patients who tend to have a smaller amplitude and advanced acrophase that is also more labile [32].
Given the risk associated with nocturnal hypertension [33] and with a blunted circadian variation of BP [11,12], a new class of drugs called angiotensin receptor neprilysin inhibitor (ARNI) has roused interest. Sacubitril/valsartan is the first agent approved in this new class of drugs by the Food and Drug Administration to treat patients with chronic heart failure with reduced ejection fraction in NYHA class II, III, or IV. It is used instead of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and in conjunction with other standard treatments for heart failure (beta-blocker or aldosterone antagonist) [34]. Interestingly, the effects of this medication were investigated on the 24-h BP profile of patients with mild-to-moderate hypertension and in patient subgroups based on their nocturnal BP dipping status [35]. Taken once daily in the morning for 8 weeks, 200 or 400 mg of sacubitril/valsartan compared to 20 mg olmesartan showed the ability of sacubitril/valsartan to reduce the 24-h BP and to maintain the dipper pattern of nocturnal BP, features that are important to attenuate or prevent hypertension-mediated target organ damage and associated conditions [35]. The study involved 24-h ABPM on 632 Japanese patients, all treated in the morning. Average global results characterizing all patients in the study are impressive. Whether other treatment times may yield even better results, and whether treatment in the morning as administered in this study may affect some of the patients in an undesired way (e.g., by modifying BP toward a more risky 24-h BP pattern) remain unanswered questions. Our re-analyses herein aimed at calling attention to these questions, the importance of which we addressed based on weeklong monitoring in relation to five other anti-hypertensive drugs and one drug combination.
Most studies using ABPM are limited to 24 h, for several reasons: cost, insurance coverage issues, and the burden to patients who resent the repeated squeezing of the arm by the cuff. Despite efforts to develop noninvasive cuff-less BP monitoring devices, fundamental questions regarding their accuracy, performance, and implementation remain to be addressed before they can be recommended for clinical use, as concluded by the European Society of Hypertension Working Group on BP Monitoring and Cardiovascular Variability [36]. A home BP monitor capable of taking three measurements during nighttime sleep (Omron HEM 747-IC-N, Omron Life Science Co., Tokyo, Japan) [37] (available in Japan but not in the USA), combined with manual measurements taken with the device at different times of the day, would be more affordable and better tolerated, and could be used for several consecutive days. Should built-in software for the as-one-goes chronobiologic interpretation of the data thus collected be developed and implemented, true health surveillance could be achieved not only for hypertensive patients in need of treatment but also for every citizen as a true preventative endeavor [38].
Through illustrative examples, several issues were raised to bring attention to inter-individual differences in the response to timed treatment, which may account for the lack of consensus in recommending a preferred treatment time [1,2], and to the merits of personalizing treatment timing. First, the large diversity of circadian patterns of BP in the absence of treatment needs to be recognized. The optimal treatment time is likely to markedly differ between a patient whose BP peaks during the nightly rest span and a patient with an excessive 24-h amplitude of BP that peaks during the daytime. In the former case, treatment needs to be most effective to reduce BP during sleep, whereas doing so in the latter case may be harmful and treatment should aim at reducing the high values during the awake daytime. Second, awareness of the multiple factors affecting BP that are responsible for the large day-to-day variability in all aspects of the circadian pattern of BP mandates that monitoring be carried out over several days in association with each treatment time tested. Third, in view of the greater reproducibility of the 24-h amplitude-phase over the day-night (or night-day) ratio to identify abnormal circadian BP patterns, chronobiologic reference values are urgently needed to determine whether estimated parameters are within or outside norms of their sex-, age- and ethnic-matched healthy peers. A repository of such norms made freely available would gain greater acceptance than our in-house derived reference values. Fourth, monitoring devices should include in their software the estimation of circadian characteristics (MESOR, 24-h and 12-h amplitudes and acrophases, together with a dipping classification) to help clinicians make an informed decision.
The proposed approach may seem impractical today, but the time is now to prepare for a future when unobtrusive, noninvasive wearables will be able to collect BP data automatically around the clock on a long-term basis and analyze them as-one-goes for true continued health surveillance. It will then become possible to learn about things that may be stressful and should be avoided or actions that help relaxation and could be encouraged. It could also capture changes that occur as a function of aging and distinguish them from alterations related to the development of health conditions like renal impairment, also assessing the response to treatment [9,32]. Clinical trials could address different, more pertinent questions then, no longer simplistically asking whether treatment is better in the morning (upon awakening) or in the evening (at bedtime), but instead examining whether a personalized chronobiologic approach (with patients treated at their own best time, which can differ from one patient to another) is superior to current conventional practice.
Authors’ contributions
Study design (YW, GC); statistical data analysis (GC, LAB, KO); clinical relevance (KO, YW); writing, editing and revising (GC, KO, YW, LAB).
Ethics statement
Data from previously published studies [23,24] are re-analyzed herein.
Data availability statement
Data analyzed herein are available from the corresponding author on reasonable request.
Submission declaration
All analyses, figures and tables are original. They have not been published previously and are not submitted for publication elsewhere.
Declaration of generative AI in scientific writing
We did not use AI.
Support
Halberg Chronobiology Fund (GC).
Declarations of competing interests
None.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data analyzed herein are available from the corresponding author on reasonable request.