Hypertension is estimated to account for up to 6% of deaths worldwide,1 and is the most commonly treated modifiable risk factor for cardiovascular disease (CVD). There is a clear relationship between reducing blood pressure for hypertensive patients and reduction in cardiovascular death and mortality, although this benefit may be attenuated with multi-morbidity and age.2

Clinical guidelines in the UK,3 and further afield,4 have recommended that a diagnosis of hypertension is made using ambulatory blood pressure monitoring (ABPM). Among the benefits of ABPM is the ability to examine night-time blood pressure and the nocturnal dip in blood pressure. Clinicians should consider the magnitude of the nocturnal reduction of blood pressure, and patients ‘dipping’ less than 10% at night are at an increased CVD risk.5

Observational studies have demonstrated that night-time ambulatory blood pressure is a better predictor of CVD events than either in-office blood pressure or daytime blood pressure.6,7 In particular, blunted nocturnal decline in blood pressure has been documented as being a risk factor for cardiovascular mortality in the general population, in addition to patients with other CVD risk factors.8

Blunted nocturnal dipping of blood pressure is particularly marked for patients with chronic kidney disease (CKD) and diabetes, secondary to vascular calcification and hyperglycaemic damage respectively, which may be a component in explaining why cardiovascular morbidity is higher in these clinical groups.

Evidence to date

With such data, there has been recent clinical interest in whether patients may benefit from having antihypertensive medications prescribed at night rather than first thing in the morning. In the 2010 MAPEC trial, a 5.6 year duration study (n= 2156 hypertensive patients, 52% female, mean age 56, 20% had diabetes, and 13% smoked), patients were randomised to take antihypertensive medications upon awakening or to take one or more medications at bedtime (47% took medications at bedtime).9

Daytime blood pressure for both groups was approximately 125/75mmHg, with night-time blood pressure 5/2mmHg lower in the bedtime medication group than the morning medication group (111/63mmHg versus 116/65mmHg).There was a statistically significant reduction in mortality (morning 2.6% versus bedtime 1.1%) and total CVD events (morning 17.3% versus bedtime 6.3%).9 There were several limitations in the study including the lack of blinding, no correction for multiple analyses and CVD event rates were inexplicably higher than expected (very uncommon in clinical trials).9

A Cochrane systematic review analysed 21 randomised control trials of various blood pressure medications, and reported that taking blood pressure medications in the evening versus morning resulted in a greater 24-hour blood pressure reduction (1 to 2mmHg) in most antihypertensive classes, although the clinical significance of this is as yet unclear as no randomised controlled trial reported on clinically relevant outcome measures.10 However, the authors reported no significant difference in overall adverse events and withdrawals due to adverse events among evening versus morning dosing regimes, a commonly quoted reason for trialling bedtime dosing regimens.10

New study

The Hygia Chronotherapy Trial, conducted within the clinical primary care setting, was designed to test whether bedtime in comparison to usual upon awakening hypertension therapy exerts better cardiovascular disease (CVD) risk reduction.11

It randomised 19,084 patients to taking their pills on waking or at bedtime, and it has followed them for the longest length of time – an average of more than six years – during which time the patients’ ambulatory blood pressure was checked over 48 hours at least once a year.

The researchers had adjusted their analyses to take account of factors that could affect the results, such as age, sex, type 2 diabetes, kidney disease, smoking and cholesterol levels.

When they looked at individual outcomes, they found that the risk of death from heart or blood vessel problems was reduced by 66%, the risk of myocardial infarction was reduced by 44%, coronary revascularisation by 40%, heart failure by 42%, and stroke by 49%.

Routine ingestion by hypertensive patients of ≥1 prescribed blood pressure-lowering medications at bedtime, as opposed to upon waking, resulted in improved ABP control (significantly enhanced decrease in asleep blood pressure and increased sleep-time relative blood pressure decline, i.e. dipping) and, most importantly, markedly diminished occurrence of major CVD events.

Clearly diuretic medications are inappropriate to prescribe at night, but shorter-acting calcium channel blockers, beta-blockers and ACE inhibitor/ARB medications may provide improved blood pressure control alongside reduced side-effect profile. It would be advisable to consider using ABPM to reassess patients blood pressure to see if medication regimen changes is associated with improvements in diurnal blood pressure, as there is data to suggest that ABPM can be used in this setting with good effect.

Given the current financial climate, cost neutral approaches to try and improve the management of hypertension and associated sequelae are certainly worth considering for the appropriate patient. Chronotherapy may be one such approach.

 


Lloyd Hughes
GP Registrar, NHS Fife

 


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3. NICE. Hypertension: clinical management of primary hypertension in adults www.nice.org.uk/CG127 (accessed 13/05/17)

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6. Kikuya M, Ohkubo T, Asayama K, et al. Ambulatory blood pressure and 10-year risk of cardiovascular and noncardiovascular mortality: the Ohasama Study. Hypertension 2005; 45(2): 240–45

8. Ohkubo T, Hozawa A, Yamaguchi J, et al. Prognostic significance of the nocturnal decline in blood pressure in individuals with and without high 24-h blood pressure: the Ohasama study. J Hypertens 2002; 20: 2183–189

9. Hermida RC, Ayala DE, Mojon A, Fernandez JR. Influence of circadian time of hypertension treatment of cardiovascular risk: results of the MAPEC study. Chronobiol Int 2010; 27(8): 1629–51

10. Zhao P, Xu P, Wan C, Wang Z. Evening versu8s morning dosing regimen drug therapy for hypertension. Cochrane Database Syst Rev 2011;(10): CD004184

11. Hermida RC, et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. doi/10.1093/eurheartj/ehz754/5602478"