Chronotherapy for Hypertension: Improvement in Patient Outcomes With Bedtime Administration of Antihypertensive Drugs

Pankaj Mathur; Sabeeda Kadavath; James D. Marsh; Jawahar L. Mehta


Eur Heart J. 2020;41(48):4577-4579. 

In This Article

Abstract and Introduction


Hypertension is a silent killer and is the leading preventable risk factor for premature death and disability worldwide.[1] According to the latest US Center for Disease Control (CDC) report, hypertension is prevalent in 29% of adults aged 20 and over, and the prevalence increases to 63% of subjects 60 years and over.[2] Several factors, including excess calorie intake, obesity, sedentary lifestyle, and physical and emotional stress, contribute to its rising prevalence to epidemic proportions around the world. It is well established that patients with both hypertension and diabetes are at much higher risk of atherosclerotic cardiovascular disease and chronic kidney disease, especially women.[3]

Effective blood pressure management has been shown to decrease the incidence of stroke, heart failure, major cardiovascular events, and all-cause mortality. Further, the reductions of stroke, major cardiovascular events, and cardiovascular death are all proportional to the reduction of systolic and diastolic blood pressure and independent of the class of antihypertensive medications.[4] Unfortunately, healthcare disparities in hypertension management are staggering. According to a study by Mills et al. in 2010,[5] worldwide only 46.5% of adults with hypertension were aware of their condition, 36.9% were treated with antihypertensive medications, and only 13.8% had their blood pressure controlled. Predictably, awareness, treatment, and control of hypertension were low in low- and middle-income countries, leading to poor outcomes. Several strategies, including health promotion, education, and simplification of the antihypertensive drug regimen, may help in medication adherence and improved outcomes.[5]

The circadian changes in blood pressure play an important role in various pathophysiological conditions. Normally diurnal variation with higher blood pressure in the early morning and a decline in blood pressure in the late evening, particularly during sleeping hours, has been well described. These have been called the dipper and non-dipper blood pressure patterns.[6] Several physiological mechanisms, such as circadian rhythm in monoaminergic systems along with changes in hypothalamic–pituitary–adrenal, hypothalamic–pituitary–thyroid, renin–angiotensin–aldosterone systems, and a host of biological alterations regulate blood pressure and induce a circadian variation.[6] The non-dipper pattern of blood pressure has been attributed to reduced glomerular filtration capability commonly seen with chronic kidney disease in the African-American population,[7] and enhanced tubular sodium reabsorption commonly seen with primary hyperaldosteronism and metabolic syndrome leading to nocturnal hypertension in these patients. Low baroreceptor sensitivity also alters physiological variation in blood pressure and results in metabolic syndrome.[8]

In this context, studies have shown that elevated night-time ambulatory blood pressure is closely linked with fatal and non-fatal cardiovascular events such as stroke, myocardial infarction, and cardiovascular death.[9–11] Nocturnal hypertension is also an independent predictor of cognitive dysfunction, chronic kidney disease, and endothelial dysfunction in hypertensive patients. Night-time blood pressure reduction is often neglected but is of considerable importance in the goal of reducing cardiovascular events, especially in patients taking antihypertensive medications. This leads to the question of the appropriate timing of taking antihypertensive drugs.

Several studies have shown the benefits of bedtime administration of antihypertensive medications in various patient populations. Hermida et al.[12,13] studied 2012 hypertensive patients without diabetes, and showed that bedtime ingestion of antihypertensive medications reduced the risk of new-onset diabetes[12] and incident chronic kidney disease.[13] Wang et al.[14] in a meta-analysis comprising 3732 patients observed that bedtime administration of medications was effective in lowering blood pressure in non-dippers among chronic kidney disease patients. Bowles et al.[15] reviewed this topic and observed an improved 24-h blood pressure and dipping blood pressure profile, with at least one medication taken in the evening. The Japan Morning Surge-Target Organ Protection (J-TOP) open-label multicentre trial of 450 patients showed that reduction in night-time home blood pressure with an evening dose of the angiotensin receptor blocker candesartan was significantly correlated with a decrease in left ventricular hypertrophy[16] and microalbuminuria.[17]

The study reported by Hermida et al.[18] in this issue of the European Heart Journal is a multicentre prospective, open-label trial in almost 20 000 hypertensive patients in a primary care setting, making it one of the most extensive studies of its kind. Patients were asked to take their antihypertensive medications either at bedtime or soon after awakening. This trial had a good representation of all age groups and both genders. Additionally, ambulatory blood pressure was monitored for 48 h and, the patient follow-up was quite long, i.e. 6.3 years. The most remarkable result noted in this trial was a 45% reduction in cardiovascular events with ingestion of the entire daily dose of blood pressure-lowering medications at bedtime compared with the morning intake. The bedtime administration of blood pressure medications was also associated with improved renal function, lower prevalence of non-dippers, lower LDL-cholesterol, and higher HDL-cholesterol.

There are several strengths and weaknesses of this study. Inclusion of a large number of primary care patients of both genders followed for a long time, receiving a variety of antihypertensive medications are major strengths of the study. Additionally, the study establishes in a large population that bedtime administration of antihypertensive medication is safe. There was no increase in nocturnal hypotension and potential sequelae such as falls. On the other hand, this study included only a Caucasian population in Spain. Further studies in multiracial groups need to be conducted before the routine bedtime intake of antihypertensive drugs can be recommended widely. Secondly, this study by design could not determine the effect of bedtime vs. morning intake of antihypertensive drugs in dippers and non-dippers on cardiovascular outcomes (Take home figure).

Take home figure.

Chronotherapy for hypertension: pathophysiology, benefits, and concerns.