People who took their blood pressure medications at bedtime were 45% less likely to experience a major cardiovascular outcome, such as heart attack or stroke, compared with people who took them in the morning.
Most blood pressure medications, diuretics aside, do not have a recommended time of administration. A large trial conducted across 40 general practices in Northern Spain assigned 19,084 adults to take their blood pressure medications either in the morning or at night. Over an average of six years, there was a clear, reduced risk for the combined outcome, with similar risk reductions for each event. The effect seemed to be mediated by the improved night-time blood pressure control, which supports previous theories on the topic.
It may still be preferable to take diuretics in the morning, but for most blood pressure medications, this could be a potentially beneficial change.
Why was this study needed?
Hypertension for most people is defined as a clinic blood pressure of 140/90mmHg or greater, combined with ambulatory or home measurements averaging 135/85mmHg or higher. The Global Burden of Disease (2015) highlighted hypertension as the third-largest modifiable risk factor for disease in the UK after tobacco smoking and poor diet. It is the single greatest risk factor for cardiovascular disease.
Nearly 9.8 million people were recorded on the UK hypertension register in 2017/18. In the same year, 246 people per 100,000 in the UK died from cardiovascular disease (age-standardised) and 1.8 million received hospital treatment. Hypertension was estimated to account for 45% of all cardiovascular deaths and 48% of cardiovascular disability.
Several past trials have indicated that taking hypertensive medications before bed may normalise night-time blood pressure and improve overall 24-hour control. This trial aimed to test this theory and see whether taking all hypertensive medications at bedtime could reduce cardiovascular risk.
What did this study do?
The Hygia Chronotherapy randomised controlled trial was conducted across 40 general practices in Northern Spain as part of a larger project looking at ambulatory blood pressure measurement. Over 10 years, 19,168 adults taking one or more anti-hypertensive medications were randomised to take them in the morning or at night.
Average patient age was 61 years, 56% were male, 43% had obesity, 24% type 2 diabetes, 29% chronic kidney disease, and 10% had previously had a cardiovascular event.
In total, 53% were taking angiotensin receptor blockers (ARBs), 25% ACE inhibitors, 33% calcium channel blockers, 22% beta-blockers and 47% diuretics. ARBs or ACE inhibitors were the most common single therapies, with the addition of a diuretic or calcium channel blocker the most common dual combinations.
Patients were followed up by clinical assessments and 48-hour ambulatory blood pressure monitoring at least annually. The outcome assessors were unaware of group allocation.
What did it find?
- Over an average 6.3 years of follow-up, 9% of patients (1,752) experienced one of the main cardiovascular outcomes of interest: heart attack, revascularisation procedure, heart failure or stroke, or related death.
- Patients taking their medications at bedtime had 45% reduced risk of this composite outcome; hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.50 to 0.61 (with adjustment for baseline characteristics including night-time blood pressure variation).
- Patients taking medication at bedtime also had reduced risk of all individual outcomes assessed, including cardiovascular death (HR 0.44, 95% CI 0.34 to 0.56), heart attack (HR 0.66, 95% CI 0.52 to 0.84), revascularisation procedure (HR 0.60, 95% CI 0.47 to 0.75) and ischaemic stroke due to a clot (HR 0.54, 95% CI 0.42 to 0.69). The only exception was a transient ischaemic attack (secondary outcome), which was not statistically significant.
- 48-hour blood pressure monitoring demonstrated that both systolic (upper figure) and diastolic (lower figure) blood pressure dipped lower during the night for patients taking their medication before bed. There was no difference in daytime blood pressure.
- There was no difference in the frequency of adverse effects (reported by around 6% of each group), or patient adherence to the allocated treatment schedule (about 3% of each group showed poor adherence).
What does current guidance say on this issue?
NICE hypertension guidelines (2019) cover the diagnosis of the condition and assessment of cardiovascular risk. Recommendations are given on starting antihypertensive medication alongside lifestyle adjustment, stepwise selection of drug treatment, and ongoing monitoring.
No recommendations are given on the timing of drug administration.
What are the implications?
This trial builds on previous research findings, adding strength with its large sample size and long duration of follow-up. This was a well-conducted trial in primary care, and it was not possible to analyse whether there may be a difference according to drug regimen and/or associated patient characteristics.
The findings seem to provide strong evidence. Unless there is a reason to take antihypertensive medications at another time of the day, taking them at bedtime may be beneficial and is not expected to cause harm.
Citation and Funding
Hermida RC, Crespo JJ, Domínguez-Sardiña M et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Heart J. 2019;Oct 22. doi.org/10.1093/eurheartj/ehz754. [Epub ahead of print].
Funding was provided by the Spanish government.
British Heart Foundation. Heart and circulatory disease statistics 2019. London: British Heart Foundation; 2019.
NICE. Hypertension in adults: diagnosis and management. NG136. London: National Institute for Health and Care Excellence; 2019.
Public Health England. Health matters: combating high blood pressure. London: Public Health England; 2017.
Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre