The drugs do work….better at bedtime

Introduction

The results of many important trials were published in 2019 such as DAPA-HF,¹ PARTNER-3,² COACT.³ The Hygia Chronotherapy trial stands out as it suggests that a small change in clinical practice can have a huge impact on patients with a 45% reduction in death from cardiovascular disease.⁴

Hypertension (HTN) is the leading cause of cardiovascular mortality and morbidity worldwide. In 2015, it accounted for almost 10 million deaths and over 200 million disability-adjusted life years.⁵ Untreated HTN can lead to target end-organ damage such as stroke, myocardial infarction, chronic kidney disease and hypertensive retinopathy. In 2015 the global prevalence was estimated to be 1.13 billion people with over 150 million in Europe.⁶ By 2025 it is estimated that 1.5 billion people will have HTN.⁶ The European Society of Cardiology (ESC)/European Society of Hypertension define HTN as a blood pressure >140/90 mmHg,⁶ whereas the American College of Cardiology/American Heart Association define HTN as >130/80 mmHg,⁷ with treatment goals being <140mmHg and <130/80 mmHg respectively.

Why is BP control important at night-time?

Multiple independent studies and meta-analyses have shown that mean BP whilst sleeping is a significantly more sensitive prognostic marker of cardiovascular disease (CVD) risk compared to day-time BP measurements, clinic BP measurements or 24 hour mean BP.^8–11 In addition, clinical trials have demonstrated an improvement in BP whilst asleep and 24 hour BP patterns when anti-hypertensive treatments are taken at bedtime rather than when awakening.^12,13

It is well known that there is a circadian decrease in BP during sleep, known as the ‘night-time dip’. It is defined as the difference between mean systolic pressure in the daytime and mean systolic pressure at night-time (expressed as a percentage of the daytime mean). The accepted normal ‘night-time dip’ is between 10-20%. This dip is a recognised measure of cardiovascular risk. Non-dippers (i.e. no dipping response) have increased cardiovascular risk and higher mortality.^14,15 The definition of a ‘non-dipper’ is having a night-time BP that decreases by <10% compared to daytime BP.¹⁶

There are certain features of circadian changes in BP that may cause harm. Firstly, the early morning BP surge. It is well documented that in the early morning, BP rises sharply in response to the activation of the sympathetic nervous system.^17,18 Other haemodynamic and neurohormonal changes occur which include increases in blood viscosity, vascular tone and heart rate with a decrease in vagal activity.¹⁶ There is an increased incidence of acute coronary syndromes, stroke and sudden death in the morning in patients with HTN and post-awakening morning surges in BP.¹⁹ The renin-angiotensin-aldosterone system (RAAS) also plays a huge role in BP control. It has been found that peak activity of the RAAS occurs during sleep.²⁰ Non-dipping patterns of BP and the early-morning BP surge are mediated by RAAS activation, volume excess and the sympathetic nervous system. In light of these factors, it would make sense to use antihypertensive agents at night-time.

Hygia Chronotherapy Trial

Study design

The Hygia project is a research network comprising 40 primary care centres with the aim to incorporate ambulatory blood pressure monitoring (ABPM) as the main method to diagnose hypertension and assess treatment response. The project is managed by the Research and Coordinating Centre at the University of Vigo, Spain. The Hygia Chronotherapy Trial hypothesised that ingestion of the entire daily dose of anti-hypertensives at bedtime leads to better ABPM control and CVD risk reduction compared with ingestion in the morning upon waking. The Hygia trial was funded by the Ministry of Science and Innovation, Government of Spain.

The Hygia Trial was a prospective, multi-centre (40 centres), randomised open-label, blinded endpoint-controlled trial with patients distributed in a 1:1 ratio into two parallel arms defined according to the circadian time of treatment (awakening treatment group versus bedtime treatment group).⁴ Patients were informed to place their medication at the bedside table and take immediately on waking from night-time sleep or immediately before lights-out. ABPM criteria were used to define HTN with patients requiring at least one of the following: awake SBP mean≥135 mmHg, awake diastolic BP (DBP) mean≥85 mmHg, asleep SBP mean≥120 mmHg, asleep DBP mean≥70 mmHg. Inclusion and exclusion criteria are summarised in Table 1.

The primary endpoint was a composite of CVD death, myocardial infarction, coronary revascularization, heart failure and stroke (ischaemic and haemorrhagic).²¹ Individual analysis also occurred for secondary endpoints of stroke, coronary events (CVD death, myocardial infarction and coronary revascularisation) and cardiac events (coronary events and heart failure).⁴

At the start of the study and at every follow-up clinic, at least 3 consecutive BP measurements were taken when the patient had rested in a seated position for at least 10 minutes. 48-hour ABPM was then applied. 48-hour measurements were felt to be more reliable compared to 24-hour ABPM as this would optimise reproducibility of the results. Thirteen different BP measurements and variables were analysed which included: office BP and heart rate, mean 48-hour BP, awake and asleep BP and non-dipper. Medications were reviewed and optimised if required at follow-up.

Study outcomes

Patients were recruited from 2008-2018. In total 22 654 patients with known hypertension were screened, with 2879 (12.7%) excluded who were initially thought to be hypertensive but were found to be normotensive on ABPM, 607 (2.7%) excluded due to invalid baseline ABPM and 84 (0.4%) patients disqualified because of less than the required 1-year follow-up. After exclusion, 19 084 (84%) patients (56% male, mean±SD 60.5±13.7 years, 43% obesity, 29.4% chronic kidney disease, 23.9% type 2 diabetes) were allocated to either treatment on awakening (n=9552) or treatment at bedtime (n=9532). Both groups were well matched following randomisation.

The most commonly prescribed monotherapy in both treatment arms were angiotensin-2 receptor blockers (ARB) (53.1%), calcium channel blockers (CCB) (34.8%) or angiotensin converting enzyme-inhibitors (ACEi) (24.4%). The most common dual combination treatments were ARB/ACEi with a diuretic (43%) and the most common triple therapy was ARB/ACEi with diuretic and CCB (69%). The final analysis observed that patients in the bedtime group took significantly fewer medications than the awakening group (1.8±0.89 in the awakening group versus 1.71±0.93 in the bedtime group p<0.001). There was a significant difference in the 10 out of 13 different BP measurements and variables all in favour of the bedtime group. For example, the mean 48-hour systolic BP was 125.6±14.5 mmHg in the awakening treatment group compared to 124.3±12.9 mmHg (p<0.001) in the bedtime treatment group. The authors found that the decrease in the asleep systolic BP was the most significant predictor of reduced CVD risk. Interestingly, the incidence of non-dipper patients reduced significantly in the bedtime group.

After a median follow-up of 6.3 years, 3246 (17%) patients had a registered event; 1752 (9.2%) experienced the primary composite outcome (myocardial infarction n=274, coronary revascularisation n=302, heart failure n=521, stroke n=345, CVD death n= 310). Bedtime-treatment patients had a significantly lower hazard ratio (HR) of the primary CVD outcome compared with the awakening-treatment patients (HR 0.55, 95 % confidence interval (CI) 0.50-0.61; p<0.001). For the secondary endpoints which were analysed separately, there was a significant reduction in all components (p<0.001): CVD death (HR 0.44, 95% CI 0.34-0.56); myocardial infarction (HR 0.66, 95% CI 0.52-0.84); coronary revascularisation (HR 0.60, 95% CI 0.47-0.75); heart failure (HR 0.58, 95% CI 0.49-0.70); and stroke (HR 0.51, 95% CI 0.41-0.63).

In the original publication the authors only reported the relative hazard ratio and not the absolute risk reduction (ARR) or the number needed to treat (NNT). Following criticism, the authors responded by publishing the data on the ESC website.²² The authors quoted that the total CVD events in the awakening treatment group was 1566, and in the bedtime treatment group was 888, with an ARR 7.08 (95% CI 6.13-8.02) and NNT 14.13 (95% CI 12.46-16.30).

Discussion

This is the first study of its kind with long-term follow-up and a large sample size to assess true differences in a real-world primary care setting which are its major strengths. The authors and readers could conclude that the significant 45% reduction in CVD outcome was achieved by the ingestion of all anti-hypertensives at bedtime and the pathophysiological circadian rhythm of BP regulation. In addition, there were improvements in renal function and cholesterol levels (LDL and HDL) observed with bedtime administration. This study is consistent with previous findings investigating bedtime administration of anti-hypertensive agents.^23,24

Patient compliance of the anti-hypertensive was better in the bed-time group, apart from diuretics (likely due to the inconvenience of nocturnal diuresis). The results of the trial could reflect that patients were less likely to forget taking their tablets at bedtime as opposed to on wakening. Drug treatment at bedtime was shown to be safe, with no difference in nocturnal hypotension (39 patients in the awakening group and 26 patients in the bed-time group) or reported falls.

One limitation was the homogenous patient population in the study group. Further studies are required in different ethnicities, especially South-Asian and Afro-Caribbean cohorts. Assessing those who work shift-patterns would also be useful as these were excluded from the present study. Another relevant feature was that the patients’ treatment was chosen by their physicians according to current clinical guidelines which reflect the real-world and were not assigned specific anti-hypertensive classes or specific drugs to use within each class.

Conclusions

The Hygia Chronotherapy trial has demonstrated that taking anti-hypertensive agents at bedtime significantly reduced CVD morbidity and mortality. Guidelines may change as a consequence of this study in due course. Another major point is that this change is cost-neutral and the bedtime patient group had better compliance and ingested less tablets. The results may appear to be too good to be true, but a simple switch in timings is worth it, which we can all do from tomorrow apart from the diuretic!

Disclosures

None.

References

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