Timing of Once-Daily Blood Pressure Medications Does Not Influence Cardiovascular Outcomes, Study Finds

Nearly half of adult Americans have hypertension (blood pressure values that are consistently above normal), putting them at risk of cardiovascular disease (such as heart attack and stroke).[1] This is because hypertension damages the lining of the arteries, making them more susceptible to the buildup of plaque and its subsequent complications.

The good news is that strong research evidence demonstrates that controlling high blood pressure — with healthy lifestyle modifications and, when needed, use of antihypertensive (blood pressure-lowering) medications — reduces the risks of cardiovascular disease and death.[2] This favorable effect of lowering blood pressure occurs in patients with various high blood pressure levels and underlying conditions.

In recent years, there has been a debate about when patients should take their antihypertensive medications. Generally, patients took their once-daily antihypertensive medications in the morning (hereafter, morning dosing) in clinical trials supporting the approval of these medications. However, evening dosing of these medications has been hypothesized to reduce blood pressure at night and diminish its increase in the morning,[3] possibly lowering the risk of cardiovascular disease. Although two previous studies (called Hygia[4] and MAPEC[5]) by the same key group of Spanish researchers reported an unusually high protective effect of bedtime dosing of once-daily antihypertensive medications on cardiovascular outcomes compared with morning dosing, the validity of these studies has been questioned.[6],[7]

In contrast to the findings of these Spanish studies, a recent large-scale, well-designed British clinical trial — that is likely representative of internet-savvy hypertension patients treated in primary care offices in general — showed no greater benefit of evening dosing over morning dosing of once-daily antihypertensive medications in terms of major cardiovascular outcomes. This new trial — called the TIME study — was funded by the British Heart Foundation and published in the Oct. 22, 2022, issue of The Lancet.

The TIME study details[8]

This British study was a prospective, randomized, open-label but blinded-endpoint clinical trial. It enrolled 21,104 adult hypertension patients who were taking at least one once-daily antihypertensive medication. Each of these patients was registered with a general practitioner in the U.K. and had an email address, because the study follow-up was done by email and through an online study portal. The average age of patients at enrollment was 65 years, 58% of them were men and 91% were White.

Trial staff randomly assigned 10,601 patients to take all their usual once-daily antihypertensive medications in the morning (between 6 a.m. and 10 a.m.) and assigned the remaining 10,503 patients to take these medications at night (between 8 p.m. and midnight). The specific antihypertensive medications taken by each patient were prescribed by their treating health care professional. The researchers noted that they had no reason to believe that the choice of these medications was affected by participation in the trial.

The study patients completed periodic online questionnaires that asked them, or their alternative contacts if they did not respond, about their adherence to their assigned time of taking antihypertensive medications and whether they experienced specific medication-related adverse events or certain cardiovascular-event endpoints. An independent committee of cardiology and stroke doctors that was blinded to the group assignment of patients verified the study endpoints using national death and hospitalization databases.

After a median follow-up of five years, the researchers found that patients in the morning- and night-dosing groups had similar rates of the study’s primary endpoint (a composite of vascular-related death, or hospitalization for nonfatal heart attack or nonfatal stroke). Specifically, this primary endpoint occurred in 3.7% of morning-dosing patients and 3.4% of evening-dosing patients. Likewise, no statistically significant differences between the two groups were seen in additional analyses, which divided the patients into subgroups based on their age, sex, smoking status, history of diabetes or cardiovascular disease and specific types of their blood pressure medications.

Importantly, the number of hospitalizations for glaucoma was a secondary endpoint for the TIME study because eye doctors were concerned that low blood pressure at night (nocturnal hypotension) — a possible adverse effect of night dosing of antihypertension medication — might worsen glaucoma outcomes. However, there was no difference in the number of patients reporting any glaucoma that required hospital admission between the study groups.

In addition, no major safety concerns were found in the study groups. However, diarrhea, dizziness or light-headedness, muscle aches, and indigestion or upset stomach occurred more commonly among patients in the morning-dosing group. In contrast, excessive visits to the toilet during the day or night occurred more commonly among patients in the evening-dosing group.

Overall, the TIME study researchers concluded that although their study was large enough to have detected clinically important differences in cardiovascular events between the two groups, they found “no advantage” of evening over morning dosing of once-daily antihypertensive medications in terms of major cardiovascular outcomes or death.

Notably, there is a relevant ongoing Canadian study called BedMed — estimated to be completed by the end of 2023 — that also is comparing bedtime and morning dosing of antihypertensive medications.[9] Until results of that study are available, there appears to be no compelling reason for hypertension patients taking once-daily antihypertensive medications to change the timing of their dosing.

What You Can Do

If you take antihypertensive medications, discuss with your doctor the best time to take these medications given that current evidence shows that morning and evening administration of once-daily antihypertensive medications likely will not affect your cardiovascular outcomes. What matters most is to take your antihypertensive medications regularly at a convenient time for you that minimizes any adverse effects. Do not stop any blood pressure medication before consulting your doctor.

It also is crucial to use healthy lifestyle modifications as a first-line approach to lowering high blood pressure. These modifications include abstaining from smoking, avoiding or at least limiting alcohol consumption, avoiding long-term stress, consuming a healthy diet (particularly the Dietary Approaches to Stop Hypertension [DASH] diet or the Mediterranean diet), increasing potassium intake from foods (such as beet greens and Swiss chard)[10] and reducing sodium intake, losing extra pounds, engaging in at least 30 minutes of moderate physical activity (such as cycling, dancing, jogging, swimming or walking) every day and getting enough quality sleep at night.[11]
 

References

[1] Centers for Disease Control and Prevention. Estimated hypertension prevalence, treatment, and control among U.S. adults. March 22, 2021. https://millionhearts.hhs.gov/data-reports/hypertension-prevalence.html. Accessed March 8, 2023.

[2] Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387(10022):957-967.

[3] Ho CLB, Chowdhury EK, Doust J, et al. The effect of taking blood pressure lowering medication at night on cardiovascular disease risk. A systematic review. J Hum Hypertens. 2021;35(4):308-314.

[4] Hermida RC, Crespo JJ, Domínguez-Sardiña M, et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Hear J. 2020;41(48):4565-4576.

[5] Hermida RC, Ayala DE, Mojón A, Fernández JR. Influence of circadian time of hypertension treatment on cardiovascular risk: Results of the MAPEC study. Chronobiol Int. 2010;27(8):1629-1651.

[6] Turgeon RD, Althouse AD, Cohen JB, et al. Lowering nighttime blood pressure with bedtime dosing of antihypertensive medications: Controversies in hypertension - Con side of the argument. Hypertension. 2021;78(3):871-878.

[7] Lüscher TF. The Hygia trial: Discussions about surprising results. Eur Hear J. 2020;41(16):1600.

[8] Mackenzie IS, Rogers A, Poulter NR, et al. Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. Lancet. 2022;400(10361):1417-1425.

[9] ClinicalTrials.gov. The effect of antihypertensive medication timing on morbidity and mortality. Last updated June 16, 2022. https://clinicaltrials.gov/ct2/show/NCT02990663. Accessed March 8, 2023.

[10] Potassium: An essential but often overlooked nutrient. Worst Pills, Best Pills News. November 2021. https://www.worstpills.org/newsletters/view/1430. Accessed March 4, 2023.

[11] Mayo Clinic Staff. 10 ways to control high blood pressure without medication. July 12, 2022. https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/high-blood-pressure/art-20046974. Accessed March 8, 2023.