BARCELONA – Patients with hypertension who took their antihypertensive medication in the evening or in the morning had similar rates of cardiovascular events over the following 5 years, in the much-anticipated TIME trial.
The trial, which contradicts several previous studies suggesting that evening dosing may be better, was presented at the annual congress of the European Society of Cardiology.
“The key message from this study is that taking antihypertensive medication in the evening makes no difference at all from taking it in the morning for the prevention of heart attacks, strokes, and vascular deaths,” concluded TIME lead investigator Tom MacDonald, MBChB, MD, professor of clinical pharmacology & pharmacoepidemiology at the University of Dundee (Scotland).
The hazard ratio was 0.95 for the primary endpoint, a composite of hospitalization for nonfatal myocardial infarction, nonfatal stroke, or vascular death, in the intention-to-treat population.
Similar results, with a hazard ratio around 1, were seen for all the secondary outcomes and in all subgroups.
“There is nothing to see – not a smidge of a difference – in the primary outcome or any of the secondary outcomes,” Dr. MacDonald commented.
The study also showed that evening dosing was not harmful in terms of falls or other adverse effects. Dr. MacDonald explained that taking the medication at night could result in an increase in nocturnal hypotension that may translate into more dizziness and falls if patients get up to use the bathroom during the night. “But, if anything, there were more dizzy turns during the day. The rate of fractures and hospitalization for fractures were identical in the two groups,” he reported.
“Our take-home message is that patients can take their blood pressure tablets at any time they like – whenever is most convenient – as long as they take them. It’s probably best to get into a routine of taking your tablets at the same time every day. That way you are more likely to remember to take them – but it won’t matter if that is in the morning or in the evening,” he said.
Dr. MacDonald explained that the rationale for the study was that in some patients blood pressure does not drop at night, a group known as “non-dippers,” and nighttime blood pressure is the best predictor of bad outcomes. In addition, previous studies have suggested that evening dosing of antihypertensives reduces nighttime blood pressure more effectively than daytime dosing.
“We and others thought that giving medication in the evening so that its peak effect occurs during the night might be beneficial,” he said. “We did the trial because if it had turned out that taking tablets in the evening was beneficial, it would have been one of the cheapest and most cost-effective interventions known to man. It is a nice hypothesis and most people thought this would turn out with a benefit, but it actually didn’t.”
The study did find some differences in the blood pressure profile between the two dosing schedules.
“Our results show that when antihypertensive medication is taken in the morning, then blood pressure is higher in the morning and lower in the evening. With evening dosing, blood pressure is lower in the morning and higher in the evening. It’s not a huge difference – just 1-2 mm Hg – and this didn’t translate into any difference in outcomes,” Dr. MacDonald said.
“Ideally we need medication that lowers blood pressure effectively over the whole 24-hour period. That is where the push should be,” he added.
The TIME study randomized 21,104 patients with treated hypertension to take their antihypertensive medication in the morning or in the evening. Baseline characteristics show the average age of participants was 65 years, 14% had diabetes, 4% were smokers, 13% had prior cardiovascular disease, and mean blood pressure at entry was 135/79 mmHg.
TIME was a pragmatic study, with participants recruited from primary and secondary care registering on the Internet, and information on hospitalizations and deaths obtained from participants by email and through record linkage to national databases, with further data gathered from family doctors and hospitals and independently adjudicated by a blinded committee.
The median follow-up duration was 5.2 years, but some patients were followed for over 9 years.
The primary endpoint occurred in 362 (3.4%) participants in the evening-dosing group (0.69 events per 100 patient-years) and 390 (3.7%) in the morning-dosing group (0.72 events per 100 patient-years), giving an unadjusted hazard ratio of 0.95 (95% confidence interval, 0.83-1.10; P = .53).