By Dr Linxin Li, Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, Oxford University

This week, in the TIA clinic we have a 75-year old patient coming back for his 1-year follow-up. He is currently taking all the prescribed secondary prevention medication including two antihypertensive drugs. He has brought back his home blood pressure readings recorded over the preceding months, which consistently showed that despite relatively well-controlled blood pressure during the day, he has late evening spikes. An Ambulatory Blood Pressure Monitor (ABPM) was also fitted which suggested that he has a non-dipper pattern during sleep.

What does this mean? Should we treat his blood pressure differently, for example by changing the timing of these blood pressure medications?

It was suggested more than 4 decades ago that in healthy individuals, blood pressure follows a circadian pattern, where it starts to drop from late evening onwards, reaching a nadir around midnight and then rises up again just after awakening in the morning.1 However, this pattern can change with increasing age or occurrence of cardiovascular disease.2 With the use of ABPM, this phenomenon together with its variation is now more accurately defined and individuals who have a fall of >10% in systolic and diastolic blood pressure in the night compared to their daytime readings are defined as “normal dippers”, whereas individuals with a nocturnal fall <10% are “non-dippers” and those with a paradoxical rise at night are “reverse dippers”.2 Numerous studies have since suggested that disappearing of the relative day vs. night blood pressure ratio is associated with increased risks of cardiovascular events.3 Moreover, emerging evidence also showed that reversing the “non-dippers/reverse dippers” by switching the antihypertensive medication from first thing in the morning to the evening is possible and may reduce future risks of cardiovascular disease without an increase in adverse effects in high risk population.4

So yes, the nocturnal blood pressure pattern of our patient does matter and it is perhaps worth a trial to switch his antihypertensive drugs to the evening to see if we can better control his blood pressure.

One step further – given that the activity of the renin-angiotensin-aldosterone system, which is important in blood pressure regulation, peaks during sleep, should we give blood pressure medication to all our patients in the evening irrespective of their nocturnal blood pressure pattern anyway?

There is emerging evidence in favour of evening vs. morning dosing in patients with diagnosed hypertension. The Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares (MAPEC) study was the first trial to compare in 2156 hypertensive patients a regimen of bedtime vs. morning dosing. After a median follow-up of 5.6 years, they showed that compared with morning dosing, the bedtime regimen was associated with reduced prevalence of non-dipping and a 64% lower risk of cardiovascular events.5 More compelling evidence comes from the recent Hygia Chronotherapy Trial, which randomised in a primary care setting 19,084 hypertensive patients with a mean age of 60.5 years to bedtime vs. morning dosing. They found that during a median follow-up of 6.3 years, compared to usual morning dosing, bedtime dosing significantly increased nocturnal dipping and almost halved the risks of major cardiovascular event. The result was also consistent for reducing stroke risk (hazard ratio=0.51).6

Although promising, many questions however remain to be answered before we can confidently change the timing of all our patients taking antihypertensive medication. Does the observed effect apply in secondary prevention? What about at older ages? Does different drug class have a different effect? What about the long-term effect on cognition?

Another ongoing trial – The Treatment In Morning versus Evening (TIME) study might soon shed light on some of these questions.7 But before that, antihypertensive drugs: morning or evening? This remains a question.

 

References

  1. Millar-Craig MW, Bishop CN, Raftery EB. Circadian variation of blood-pressure. Lancet 1978; i: 795-97
  2. Mahabala C, Kamath P, Bhaskaran U, et al. Antihypertensive therapy: nocturnal dippers and nondippers. Do we treat them differently? Vasc Health Risk Manag 2013; 9:125-133
  3. Fagard RH, Thijs L, Staessen JA, et al. Night-day blood pressure ratio and dipping pattern as predictors of death and cardiovascular events in hypertension. J Hum Hypertens 2009;23:645–53.
  4. Hermida RC, Ayala DE, Mojón A, et al. Influence of time of day of blood pressure-lowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes. Diabetes Care 2011;34:1270–6.
  5. Hermida RC, Ayala DE, Mojón A, et al. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int 2010;27:1629–51.
  6. Hermida RC, Crespo JJ, Dominguez-Sardina M, et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Heart J 2019;  doi: 10.1093/eurheartj/ehz754. [Epub ahead of print]
  7. Rorie DA, Rogers A, Mackenzie IS, et al, Methods of a large prospective, randomised, open-label, blinded endpoint study comparing morning versus evening dosing in hypertensive patients: the Treatment In Morning versus Evening (TIME) study. BMJ open 2016; http://bmjopen.bmj.com/content/6/2/e010313