A 2011 Cochrane review evaluated the administration time-related effects of antihypertensive drugs administered as once-daily monotherapy on all-cause mortality, CV morbidity and mortality (primary outcome) and reduction of BP and adverse effects (secondary outcome) 61. None of the randomized-controlled trials, which fulfilled the inclusion criteria of the review, reported on the primary outcome. Compared with morning dosing, 24-h BP was significantly lower with bedtime administration. The review did not report on differences in daytime nor night-time BP. No differences in adverse events or withdrawals because of adverse events were found. The overall conclusion was that bedtime administration was superior to morning administration in achieving better BP control.
Only a few prospective trials have investigated the effects of bedtime administration of multiple antihypertensive drugs. The study designs, methods and populations, the investigated drug classes and combinations, and the BP effects show considerable heterogeneity and do not allow for unequivocal conclusions 62–68. However, at the European Society of Hypertension 2016 in Paris, data from the as yet unpublished HARMONY study by Poulter et al.69 were presented. In a randomized cross-over study with 103 patients treated with more than one antihypertensive drug, no difference in 24-h SBP was found between morning and evening dosing. Interestingly, although not significant, a reduction in night-time SBP of 1.68 mmHg was found with evening dosing. The authors speculated that this reduction could be important at the population level in relation to reducing CV events.
An association between night-time BP and urinary albumin excretion and development of chronic kidney disease has been found in several studies 70–72, including among patients with diabetes 73–80. In randomized-controlled trials with varying prevalence of diabetic patients, bedtime administration of antihypertensive drugs has been shown to reduce urinary albumin excretion 55,62,81,82.
At present, indications of improved prognosis with bedtime administration of antihypertensive drugs have primarily originated from studies not specifically designed to investigate the effects of chronotherapy on CV risk.
In the HOPE study, ramipril was found to significantly reduce CV morbidity and mortality as well as the development of overt nephropathy in patients with diabetes 83. According to the study protocol, treatment (ramipril and placebo) was administered at bedtime. The CV benefit was greater than that attributable to the decrease in office BP. A HOPE substudy evaluated ABPM data of 38 patients and found a nonsignificant reduction in office BP and ambulatory daytime BP, but a significant reduction in 24-h BP, mainly because of a highly significant reduction in night-time BP 84. Thus, it was suggested that the beneficial effects found in the HOPE study to a larger extent were related to the effects on BP over the 24-h period and that these effects were related to the administration of ramipril at bedtime.
In ASCOT-BPLA, the antihypertensive treatment regimen of amlodipine–perindopril was associated with beneficial effects on almost all CV outcomes compared with a regimen of atenolol–thiazide 85. Both treatment regimens were administered in the morning. Only about half of the between-treatment differences were explained by multivariate adjustments for postrandomization differences in CV risk factors. The ABP substudy of ASCOT found that the amlodipine–perindopril and atenolol–thiazide regimens had different effects on daytime and night-time BP 86. In the amlodipine–perindopril group, daytime BP was higher and night-time BP was lower. It was suggested that the lower night-time BP may have contributed towards the lower event rates with the amlodipine–perindopril regimen.
The MAPEC study is the only trial on the chronotherapeutic effects of antihypertensive drugs on CV risk 87. A total of 2156 hypertensive patients were randomized to take all of their antihypertensive drugs in the morning or one or more at bedtime. After a median follow-up of 5.6 years, the group taking one or more antihypertensive drugs at bedtime not only had significantly lower night-time BP but also a significantly lower relative risk of CV events.
Our research group carried out an open-label cross-over study in 41 patients with type 2 diabetes and nocturnal hypertension (night-time SBP≥120/70 mmHg) 90. In our study, we changed the time of administration of all of the individual’s once-daily antihypertensive drugs (median n=3). We found that bedtime administration not only significantly reduced night-time SBP with 7.5 mmHg but also 24-h SBP with 3.1 mmHg, the latter finding being novel.
However, more recent studies not originating from the mentioned centre have yielded interesting results. Although not a significant reduction, the effect on night-time SBP found in the HARMONY study may, as suggested by the authors, have clinical implications. In this respect, the studies by Tofé Povedano and colleagues and Rossen and colleagues 46,90 are important and even more so with respect to the effects of chronotherapy of antihypertensive drugs in diabetic patients.
Whereas the continued implementation of ABPM is challenged in some parts of the world by being a more expensive measurement technique, the use of chronotherapy may prove to be an important treatment strategy to reduce healthcare costs. If well-designed and well-executed, large-scale studies confirm the effects of bedtime administration on not only night-time BP but also 24-h BP, a chronotherapeutic approach may be a valuable instrument to improve hypertension treatment without increasing costs. This benefit is global but, of course, even more significant in low-income parts of the world with limited healthcare resources.
There are no conflicts of interest.
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