We’re all used to the flurry of questions that come after we start people on a new medication. You’re eyeing up the clock (running late…again), and about to say your farewells when the inquisition starts - ‘is it OK to have with grapefruit juice?’; ‘should I take it before or after food?’; ‘will it interact with my other medications?’. Most of these I usually bat off to the pharmacists with a knowing chuckle ‘they know much more about that sort of stuff than I do’ (I.e. PLEASE leave now I really must get on…), but when it comes to blood pressure medication and the question ‘should I take it in the morning or before bed?’ I take more interest.
There has been a lot of interest in the timing of antihypertensive medication over the past few years and this subject has come to the surface again in the form of the TIME trial, recently published in the Lancet 2022; 400: 1417–25 Oct 2022. Why the interest? Well, it all boils down to chronotherapy you see…This is the theory that you adjust when you take medications to complement the body’s natural biological rhythms to improve outcomes. And when it comes to blood pressure, there should be a natural diurnal variation with a dip in your blood pressure overnight. People that don’t have that night time dip are at a higher risk of cardiovascular disease. So, if you’ve got hypertension and you take your medications before bed (rather than the morning) this might help mitigate the ‘non-dippers’, restore the usual diurnal variation and reduce cardiovascular disease.
Step forward the HYGIA trial, a randomised trial that compared morning to evening dosing of antihypertensives and subsequent CVD outcomes. The results were impressive - a massive 45% relative risk reduction of major adverse cardiovascular events for those taking their blood pressure medications before bed. This inevitably caused quite a splash in both medical and lay media, and indeed was the subject of a Hot Topics presentation a couple of years ago. IF these results are true it would be hugely significant - it is very rare to get evidence of a ‘treatment’ that could result in such a substantial reduction in cardiovascular disease that doesn’t cost a thing. The theory and results were enticing in equal measure.
However, life is never that straightforward is it? This latest Lancet study noted ‘However, this subject is not without controversy and has resulted in heated discussions’. A number of concerns have since been highlighted about the Hygia trial both in terms of methodology and trial conditions, as well as irregularities with the trial protocol. The TIME trial aimed to test whether the results of the Hygia trial could be replicated in more of a real world setting. So what did they do?
This was a UK based, Scottish led, pragmatic prospective randomised trial which recruited just over 20,000 people with hypertension and on ≥1 BP medication to take their medications either in the morning or the evening. Mean age was ~65 years old and median follow-up was 5.2 years and the primary outcome was a simple composite of vascular death and hospitalisation for non-fatal MI and stroke. A primary endpoint occurred in 3.4% of the evening treatment group and 3.7% in the morning group, giving a hazard ratio of 0.95 (95% CI = 0.83-1.10) i.e. no significant difference between the two groups. This trial does not support the results of the Hygia trial and suggests it doesn’t matter if you take your BP medications in the morning or the evening.
As always we need to be aware of caveats with this data. The trial was conducted remotely using questionnaires and uploaded data so adherence (or otherwise) to the trial dose timings is at risk of recall bias. Secondly about 30% of participants reported ‘non-adherence’ to their stipulated dose timings at some point in trial, although this was down to ~13% at trial completion. There were higher numbers reporting non-adherence in the evening dosing group compared to morning which could dilute any potential benefits of the evening dosing. But as the authors rightly state ‘the findings probably reflect what would happen if patients in usual care were allocated to evening or morning dosing.’
The TIME trial does not support us routinely recommending patients take their antihypertensives at night, so how do we now answer the question ‘when should I take my BP meds doc?’. We do have further trials ongoing to help answer this question more definitively in the form of the Canadian BedMed trial and the associated BedMed-frail trial, which will look in more detail at side effects and safety concerns in frail populations. But in the mean time the TIME trial suggests timing of BP medications should be dictated more by concordance and side-effect profiles. Getting light headed in the morning after your ramipril dose? Try taking it before bed. But probably the most important piece of advice we can give our patients is simply to take their blood pressure medication at the time they are going to remember to take it. Lack of concordance is likely to have much more of an impact on CVD outcomes than when you take your pills.