What to recommend in clinical practice?
Outside commentators had mixed opinions on how the TIME results should be applied to clinical practice.
Discussant of the TIME study at the ESC Hotline session, Rhian Touyz, MBBCh, University of Glasgow (Scotland), said the trial asked a “very pertinent” question and the data “are certainly provocative.”
She cited several previous studies suggesting that evening dosing improved nighttime blood pressure and reduced cardiovascular events.
“The finding of no difference in event rate in the TIME study is therefore very intriguing.”
She pointed out that other studies have shown benefit of nighttime dosing in certain patient groups such as those with sleep apnea, non-dippers, and those with nocturnal hypertension.
“With all these previous data, we have to ask why the TIME trial has produced this unexpected result,” she said.
Dr. MacDonald replied that the study was completely neutral. “That is the result, and I believe it is definitive. I’m absolutely confident that we did the study as best we could. All events were adjudicated. Compliance was quite good at 60%. I can’t believe there is anything in our data that invalidates these results,” he said. “If we want to look at specific groups of patients then we have to do larger studies in those particular groups, but for a general population of hypertensive patients we didn’t find any difference at all in morning versus evening dosing.”
The TIME results are in direct contradiction of a previous high-profile study – the Hygia Chronotherapy Trial – published in 2020, which found a large protective effect of nocturnal dosing on cardiovascular events, and attracted much media attention. But this study has subsequently attracted criticism, with an “expression of concern” and a commentary raising several questions.
And a systematic review from the International Society of Hypertension published earlier this month concludes that previous trials of bedtime antihypertensive dosing had “major flaws.”
The review notes that three ongoing, well-designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing.
“Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose,” it concludes.
On the new TIME results, lead author of the ISH review, George Stergiou, MD, commented: “The benefits of bedtime dosing were not confirmed – as we well expected. So, I think bedtime drug dosing should not be routinely recommended in clinical practice.”
Although the TIME trial did not show any harms with bedtime dose, Dr. Stergiou added, “I am not too happy with their conclusion that patients should do as they wish. The vast majority of well-conducted outcomes studies which we use to guide the treatment of hypertension administered all drugs in the morning.”
One of the authors of the commentary criticizing the Hygia trial, Sverre E. Kjeldsen, MD, University of Oslo, said in an interview that the TIME trial was an important study, far more reliable than the Hygia study, and the results were as expected.
“From a scientific point of view, patients have a choice as to when to take their medication, but we strongly recommend taking blood pressure meds in the morning. Adherence is proven to be worse at bedtime. However, physicians may still consider bedtime dosing in patients proven to have high night-time blood pressure,” Dr. Kjeldsen added.
Lead investigator of the Hygia study, Ramón C. Hermida, PhD, University of Vigo (Spain), told this news organization he and his coauthors are standing by their results.
“The design and conduct of the TIME trial does not comply with the quality requirements listed in the guidelines by the International Society for Chronobiology for conducting chronotherapy trials in hypertension, and the results are not in line with the reported findings of multiple clinical trials on the effects of timed hypertension treatment on blood pressure control and circadian pattern regulation, kidney function, and cardiac pathology,” Dr. Hermida said.
Chair of an ESC press conference on the TIME study, Steen Dalby Kristensen, MD, Aarhus University Hospital, Skejby, Denmark, said he thought the trial was “very well done.”
The TIME results, he said, “are quite clear, whether you take your blood pressure tablets in the morning or the evening it makes no difference for the hard outcomes that we fear in patients with hypertension.
“I think that this solves a question that we’ve had for a long time now,” he commented. “Even though there were some changes in the blood pressure measured in the evening or in the morning it doesn’t seem to matter in terms of clinical events. This means that life might be a bit easier for patients in that they can choose when they take their medication at the time most convenient to them.
“I don’t know why previous studies suggested such a big benefit of evening dosing,” he added. “I would say the TIME trial is a more definitive result. It is a very important trial.”
Dr. Dipti Itchhaporia
Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, agreed that the TIME study was well conducted.
“On the basis of these results I wouldn’t recommend a specific time,” she said. “That’s kind of a relief, as it can be difficult to always take medications at a set time and this gives patients more flexibility.”
She suggested a possible alternative approach for patients taking more than one drug – taking one in the morning and the other in the evening. “That might give better 24-hour coverage.”
The study was funded by the British Heart Foundation. Dr. MacDonald has reported receiving research funding from Novartis and consulting fees from Novartis and AstraZeneca.
A version of this article first appeared on Medscape.com.