Bedtime Dosing of Hypertension Meds Reduces CV Events

October 31, 2019

Editor's note: The editors of the European Heart Journal added this Expression of Concern to the publication featured in this article on April 21, 2020:
"The editors would like to inform the readers of the article 'Bedtime Hypertension Treatment Improves Cardiovascular Risk Reduction: Hygia Chronotherapy Trial' by Ramon C. Hermida et al. Eur Heart J 2020; online that the content and conduct of this randomized clinical trial is currently under investigation. They therefore recommend to interpret the major results and conclusions with caution until further notice."

Taking antihypertensive medication at bedtime led to an almost halving of cardiovascular events in a new study.

The Hygia Chronotherapy Trial is the largest ever study to investigate the effect of the time of day when people take their antihypertensive medication on the risk of cardiovascular events.

The trial randomly assigned 19,084 patients to take their medication on waking or at bedtime and followed them for an average of 6 years.

Results showed that patients who took their pills at bedtime had a 45% reduction in overall cardiovascular events. This included a 56% reduction in cardiovascular death, a 34% reduction in myocardial infarction (MI), a 40% reduction in coronary revascularization, a 42% reduction in heart failure, and a 49% reduction in stroke, all of which were statistically significant.

"Our recommendations are that guidelines should consider including sleep-time blood pressure for the diagnosis of hypertension, and antihypertensive treatment should be taken at night," lead author, Ramon C. Hermida, PhD, University of Vigo, Spain, told Medscape Medical News.

"This appears to be particularly important for patients taking ACE inhibitors and ARBs [angiotensin receptor blockers] for which we found a larger benefit with bedtime dosing."

The study was published online in the European Heart Journal on October 22.

Hermida and colleagues have been working on chronobiology — using biological rhythms to increase the diagnosis, treatment response, and prevention of diseases — for the last three decades.

"In hypertension, it is logical to think about when patients take medication as blood pressure changes around the clock in symmetry with the rest/activity cycle," Hermida explained. "Many factors are involved with this variability including the renin angiotensin system being most active in the second half of sleep leading to a peak of aldosterone before waking. This led to us to believe that antihypertensive medication may be more effective when taken at night before sleep."

The group published a study last year showing that blood pressure (BP) during sleep was the major determinant of cardiovascular morbidity and mortality.

"We showed that if blood pressure is elevated during sleep then patients have increased cardiovascular risk regardless of daytime pressure, and if blood pressure during sleep is normal then cardiovascular risk is low even if the [doctor’s] office pressure is elevated," Hermida said.

The current study was conducted in primary care, with all patients having hypertension confirmed by 48-hour ambulatory BP measurement on recruitment. Doctors then assigned patients to take their medication in the evening at bedtime or in the morning upon waking.

The trial was a multicenter, controlled PROBE (prospective, randomized, open-label, blinded end point) study. Patients were allocated in a 1:1 ratio into two parallel arms defined according to the circadian time of treatment, the researchers note.

Individual doctors could choose which specific medication or combinations to use from the major therapeutic classes — ARB, ACE inhibitor, calcium blocker, beta-blocker, or diuretic. Ambulatory BP was checked over 48 hours at least once a year throughout the study and more often if medication was altered.

The two groups were well balanced at baseline in terms of comorbidities, other cardiovascular medications, and all evaluated anthropometric and clinical laboratory test variables. BP measurements were also similar in the two groups.

At the conclusion of the study, the number of prescribed hypertension medications (usually each at maximum doses) was slightly but significantly lower in the bedtime-treatment regimen. The most frequently prescribed monotherapies were ARBs or ACE inhibitors (69% of participants).

At the final evaluation, BP values were significantly lower during sleep but not during awake time in the bedtime medication group.

Results showed that during the 6.3-year median patient follow-up, 1752 participants experienced the primary cardiovascular disease (CVD) outcome (a composite of CVD death, MI, coronary revascularization, heart failure, or stroke).

After adjusting for age, sex, type 2 diabetes, chronic kidney disease, smoking, HDL cholesterol, mean asleep systolic BP, sleep-time relative systolic BP decline, and previous CVD event, patients taking their medication at bedtime showed a significantly lower risk of having primary CVD outcome (hazard ratio, 0.55; P < .001).

Hazard ratios for the individual components were CVD death 0.44; MI 0.66; coronary revascularization 0.60; heart failure 0.58; and stroke 0.51 (all P < .001).

Hermida noted that the reductions on cardiovascular events with bedtime dosing were seen with all the different classes of antihypertensive drugs used but a larger effect occurred with ACE inhibitors and ARBs. "This is relevant because of the activation of the renin angiotensin system at night," he said.

Did Ambulatory Monitoring Play a Role?

Hermida believes that in addition to the bedtime dosing, the impressive reductions in cardiovascular events may have been brought about by selection of patients with "true" hypertension detected by ambulatory monitoring.

"Ambulatory blood pressure measurement is another key part of our study," he said. "Patients who have elevated blood pressure at night may be missed if we just rely on office blood pressures. And we required periodic reevaluation by ambulatory BP monitoring to ensure that patients were not developing hypotension at night, which can be a risk factor for stroke."

The researchers report that only 39 patients in the waking group and 26 patients in the bedtime group (0.3% of all participants; P = .114 between groups) experienced sleep-time hypotension, defined by current ABPM criteria, at any time during follow-up.

In addition, there were no differences in the prevalence of patients reporting any type of adverse effects at any visit during follow-up (6.7% vs 6.0% for the awakening and bedtime-treatment regimen, respectively; P = .061).

While acknowledging that most primary care doctors do not currently have access to ambulatory BP monitoring, Hermida said: "We conducted this study in general practice and showed that with proper collaboration we can introduce ambulatory monitoring as the primary method of measuring blood pressure."

"However even in the absence of ambulatory monitoring I would say the benefits of bedtime administration would outweigh the potential adverse effects."

"While it is not my place to make clinical practice recommendations, and every individual doctor needs to make their own decision for each patient, our results suggest that changing the timing of antihypertensive medication to bedtime administration should translate into a significant reduction in cardiovascular events," he concluded.

Findings Very Clear

Commenting on the study for Medscape Medical News, Michael A. Weber, MD, professor of medicine at the State University of New York and editor-in-chief of the Journal of Clinical Hypertension, pointed out that the trial was open label, "so not as influential as a true blinded trial, but its patient numbers are large and its findings very clear."

Weber noted that previously two influential outcomes studies — HOPE and Syst Eur — showed strong cardiovascular outcomes benefits when patients were treated with nighttime dosing, but this dosing was not compared with daytime dosing. And a meta-analysis by Roush and colleagues showed significantly better outcomes with nighttime dosing than with morning dosing of hypertensive patients, "which adds further credibility to this new report," he said.

Weber added that guidelines or drug labeling have not shown a preference for morning or nighttime dosing, but some physicians may advise nighttime dosing because drugs might be better tolerated when taken in the evening since the maximum blood concentrations of the drugs would occur while patients are asleep.

"Since nocturnal blood pressure is more closely associated with cardiovascular outcomes than daytime blood pressure, it does appear reasonable that nighttime administration leading to better nighttime blood pressure control might optimize outcomes," Weber commented. "This appears to have been the case in this new study because the nighttime blood pressures were definitely reduced more than the daytime blood pressures."

"Another explanation for the advantage of nighttime drug administration is that patients might be better adherent to their therapy when taking it at night. We need more information to better explore this possibility," he added.

The Hygia Project is an independent investigator-promoted research network supported by unrestricted grants from the Spanish and Galician regional governments, and the University of Vigo. The researchers have disclosed no relevant financial relationships.

Eur Heart J. 2019;ehz754. Full text

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