Chronotherapy in Hypertension

A Pill at Night Makes Things Right?

BP, as well as many other important physiologic variables, is synchronized in a predictable manner with the circadian activity-rest cycle. Many cardiovascular, renal, and gastrointestinal functions also undergo a day–night pattern, influencing BP as well as absorption, metabolism, and elimination of antihypertensive medications. Particularly relevant is the circadian pattern of renal function, including GFR, effective renal plasma flow, and urine production, with a peak function of the first two in the daytime and a minimum at night, therefore clearing drugs that are excreted or filtered more efficiently during the day than at night.¹

The mechanisms that govern day-to-night fluctuations of kidney function and its potential relation to BP control are poorly understood, yet experimental studies suggest that novel clock-controlled genes may play a role in circadian renal control of water and sodium transport across the renal epithelia.²

The consideration of time of administration of a specific drug, also known as chronotherapy, for improvement of the response to antihypertensive therapy is not a new concept, as Bartter and coworkers recognized this more than 35 yr ago.³ Nevertheless, there is a clear lack of understanding of the mechanism, as well as the outcome implications, of applying chronobiological concepts to prescription in medicine. Many different explanations have been put forward as to why this rhythmic BP pattern is generated (melatonin, renin-angiotensin system, among others) and what goes wrong in patients that lose it (nighttime hypertension may be determined by several conditions, including high salt intake, obesity, renal dysfunction, sleep apnea, or autonomic system disturbance).⁴

As the correct time for administration of medication had not been tested in a meaningful prospective clinical trial until recently, patients are usually instructed to take their antihypertensive medications in the morning, based on a bias that was never formally tested. In recent times, some studies show evidence that elevated sleep-time BP is a better predictor of cardiovascular risk compared with awake or 24-h BP means. Hermida and coworkers recently explored this concept in several populations and show there is a relationship between the time of administration of BP medication and cardiovascular risk in several populations, including general population and type 2 diabetic individuals.^5,6

An unanswered question is whether trying to mimic the innate daily BP pattern pharmacologically would have similar cardiovascular benefits in patients with chronic kidney disease (CKD), as seen in these previously described studies in other populations. In this issue of JASN, Hermida et al.⁷ take a first step at resolving this uncertainty. In a single-center PROBE-designed trial, 661 patients with CKD were randomized into taking all once-a-day antihypertensive medications in the morning or at least one of them at night. Patients were followed with 48-h ambulatory BP monitoring (ABPM) annually, or more often if deemed necessary, for a median of 5.4 yr. The group taking ≥1 medication(s) at night was found to have lower asleep—but not awake—systolic BP, had less nondippers, and less cardiovascular events compared with the group that took all of the antihypertensive drugs upon awakening, despite taking the same amount of antihypertensive medications and obtaining similar clinic BP. Furthermore, bedtime treatment achieved a significant decrease in adjusted risk for total cardiovascular events (a composite endpoint including death, myocardial infarction, angina pectoris, revascularization, heart failure, arterial occlusion of lower extremities, occlusion of the retinal artery, and stroke) compared with outcomes of patients who took all medications upon awakening (adjusted HR 0.31; 95% CI 0.21 to 0.46; P < 0.001). Every 5-mmHg decrease in mean ABPM sleep-time systolic BP was associated with a 14% reduction in the risk for cardiovascular events during follow-up (P < 0.001), while the reduction in awake systolic BP mean was not.

This study has several strengths compared with previous trials. Most importantly, it is the first to take into account several BP measurements instead of relying on a single BP value. In addition, the fact that ABPM is performed during 48 h reduces day-to-day variability and enhances reproducibility. The authors claim that most of the beneficial effect is accomplished on lowering nighttime BP and reestablishing a normal circadian pattern while maintaining the awake-BP lowering effect. However, BP measured at the clinic at the end of the study was above commonly established targets in both groups, raising the question if similar results would be achieved if lower systolic BP goals were achieved. However, the fact that only 14.4% of cardiovascular events happened in subjects that had their sleep-time BP controlled to goal (<120/70), while 83.5% of the event-subjects had a nondipper BP profile, makes a strong argument that decreasing nighttime BP is a desirable objective.

Several other questions can be put forward. Given the fact that this study was performed in Spain, we would wonder if these results hold up in patients of different racial or ethnic backgrounds?⁸ In addition, this is a single-center study, and results were obtained on a published, yet not widely used, algorithm;⁹ therefore, there is a need to perform more studies in different populations to find out if similar outcomes can be reached with extensive use. Finally, a third issue that will need further research is whether this approach may be beneficial in essential hypertension as well as in other predominantly nondipping states, such as secondary hypertension?

As already discussed, Hermida et al. published a previous study with similar design in essential hypertension, called the MAPEC Study.¹⁰ A very impressive single-center, controlled open-label study that randomized 2156 hypertensive subjects found that a decrease in nighttime BP, by giving ≥1 antihypertensive medication(s) at night, was also associated with diminished cardiovascular events compared with those that took all their antihypertensive treatments once a day in the morning. About half of the patients were nondippers. If these cardiovascular endpoint results are reproduced and confirmed, this may very likely change ABPM utilization in clinical practice. This ABPM nighttime BP-lowering approach would make ABPM mandatory at least yearly and more often if needed. The impact on costs has to be properly evaluated, but if clinical outcomes are decreased, then it may be worthwhile pursuing this.

Of particular interest are the results concerning the so-called J-curve phenomenon. While at nighttime, a lower achieved systolic BP was always associated with lower cardiovascular risk (patients divided into quintiles), BP measured at the clinic had a J-curve shape. Similarly, as in sleep BP, there was a decrease in cardiovascular risk from the highest achieved BP quintile throughout the fourth, whereas in contrast, the lowest BP measured at the clinic was associated with an increase in cardiovascular risk. The authors claim that their BP-lowering algorithm is key in avoiding morning overdipping that occurs with clinic-guided BP reduction, and therefore the J-curve phenomenon may not apply to sleep-guided BP management.

Only two large randomized studies have been performed with evening antihypertensive medication administration—the HOPE¹¹ and the SystEur¹² trials, with ramipril and nitrendipine administered in the evening, respectively—and showed a decrease in asleep BP with fewer nondipper patients. The HOPE investigators attributed the decrease in cardiovascular events, in part, to the decrease in asleep BP. While this hypothesis is possible, and the current study by Hermida et al.⁷ adds strength and plausibility to it, this theory should be tested in a large randomized clinical trial.

An issue of clinical importance that has often been neglected by physicians before deciding the best prescription for a hypertensive patient is the half-life of the drug prescribed. It is certainly true that, quite often, a medication with a short or relatively short half-life is used as a once-a-day medication. In this case, the issue is not a chronobiology problem but inadequate timing of prescription; it is an improper medical decision that may leave a good part of the day—or probably, more often, a good part of the night—without any antihypertensive medication effect. Some of the usual medications employed to control BP have a short half-life, which precludes prescribing them only once a day. This is the case of several β-blockers, calcium antagonists, short-acting ACE inhibitors, and α-blockers, among others. It is nevertheless important to state that, in this study, all medications employed were long-acting and prescribed according to what is recommended, that is, once a day.

In summary, Hermida et al.⁷ have put pressure on the traditional morning-dose approach that has been used for many years in hypertension management, and now also in the CKD population. Their results are, without doubt, of great interest and give insight to potential chronotherapy manipulations for treatment of hypertension, prevalent in most CKD patients, and show evidence that adequate antihypertensive medication distribution during the day may improve outcomes and survival in this population. This is of upmost importance, as it has been repeatedly proven that cardiovascular complications are highly prevalent and the most frequent cause of death in CKD patients.^13–16 Nevertheless, we would certainly like to see these results confirmed or challenged in other prospective studies. In addition, the future role of ABPM may also be at stake, as more beneficial outcome results will put pressure on the economics and guidelines of ABPM use.

DISCLOSURES

None.