Introduction
Trial data
Further work
Conclusion
References

 

 

 

 

 

Introduction

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

Recent 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.

 

Trial data

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).9 There was a statistically significant reduction in mortality (morning 2.6% versus bedtime 1.1%; number needed to treat = 67) and total CVD events (morning 17.3% versus bedtime 6.3%; number needed to treat = 9).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

Although there is no large trial specifically addressing CVD for blood pressure medications taken at night, in the HOPE study ramipril was prescribed at night.11

The HOPE study was a trial looking at the effects of ramipril on cardiovascular events in high risk patients. The trial reported a 3.8% reduction in CVD in five years, which was initially assumed to be a unique property of an ACE inhibitor as the reduction of office blood pressure changed very little (3/2mmHg).11 A subsequent sub-group analysis reported that ABPM was significantly reduced (10/4mmHg, P=0.03), mainly because of a more pronounced blood pressure lowering effect during night-time (17/8mmHg, P<0.001).12

Furthermore, there is evidence that in hypertensive patients without diabetes, ingestion of one or more blood pressure-lowering medications at bedtime resulted in improved ABPM control and reduced the risk of new-onset diabetes compared to patients ingesting medications in the morning.13

Greatest benefit was observed for bedtime compared with awakening treatment with angiotensin receptor blockers (ARBs) (HR 0.39 [0.22-0.69]; p<0.001), ACE inhibitors (HR 0.31 [0.12-0.79]; p=0.015) and beta-blockers (HR 0.35 [0.14-0.85]; p=0.021).13 Similar benefits were reported in an open-label trial with patients with CKD. The authors reported that patients on bedtime treatment regimes had significantly lower mean sleep-time blood pressure and a greater proportion demonstrated ABPM control (56% versus 45%, P=0.003).14 This was of clinical relevance as each 5mmHg decrease in mean sleep-time systolic blood pressure was associated with a 14% reduction in the risk for cardiovascular events during follow-up (P<0.001).14 For patients with CKD, evening administration of antihypertensives is also associated with decreased urinary protein excretion.15

 

Further work

There is clearly further work required in order to further assess how the reduction of blood pressure secondary to administration of antihypertensive medications at night impacts clinical outcomes in patients. Given the findings of the Cochrane systematic review, it is particularly pertinent that clinical trials assess and report important outcome measures in order for this to be achieved. Further work is also needed on which agents are most suited to be prescribed at night with current data suggesting ACE inhibitor/ARB agents and some calcium channel blockers are well suited to nocturnal dosing. A further question which is relevant for prescribers is whether there is any benefit changing longer acting anti-hypertensive agents from daytime to night-time dosing, as these agents should theoretically should be unaffected by dosing timing changes.

As with many areas in clinical research, older patients are under-represented in clinical studies in this area. This is particularly important when considering whether night-time dosing reduces side-effects of some blood pressure medications, as in older multimorbid patients there may be a reduction in side-effects that has to date not been established in younger patients.

 

Conclusion

Taking one or more blood pressure medications at night rather than on waking might help manage hypertension and cardiovascular disease but given limitations in the evidence to date it is difficult to make any strong recommendations. However, in patients with particular problems with blunted nocturnal blood pressure dipping on ABPM it may be worth considering.

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 D Hughes, GP Speciality Trainee, NHS Fife

Conflict of interest: none declared

 


References

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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

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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. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Health Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342(3):145–53

12. Svensson P, de Faire U, Sleight P, et al. Comparative effects of ramipril on ambulatory and officer blood pressure: a HOPE substudy. Hypertension 2001; 38(6): e28–32

13. Hermida RC, Ayala DE, Mojon A, Fernandez JR. Bedtime ingestion of hypertension medications reduces the risk of new-onset type 2 diabetes: a randomised controlled trial. Diabetologia 2016; 59(2): 255–65

14. Hermida RC, Ayaka DE, Mojon A, Fernandez JR. Bedtime Dosing of Antihypertensive Medications Reduces Cardiovascular Risk in CKD. J Am Soc Nephrol 2011. 22(12): 2313–21

15. Mehta R, Drawz PE. Is Nocturnal Blood Pressure Reduction the Secret to Reducing the Rate of Progression of Hypertensive Chronic Kidney Disease? Curr Hypertens Rep. 2011; 13(5): 378–85