Hypertension Drug Timing Is Still Controversial: Here’s What Can Help

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Hypertension—high blood pressure—is closely related to the morbidity and mortality of cardiovascular and cerebrovascular diseases. In recent years, blood pressure monitoring and management have become more refined and individualized, but questions still remain about whether morning or evening is best to take antihypertensive drugs.

Substantial evidence suggests that nocturnal hypertension, increased morning blood pressure, and pre-morning hypertension are all associated with an increased incidence of cardiovascular disease. Many experts propose that blood pressure should be dynamically controlled 24 hours a day to reduce the adverse effects of nighttime high blood pressure. To achieve 24-hour BP control, administration of antihypertensive drugs at night or before bedtime is considered a potentially more effective strategy to control nocturnal hypertension, restore natural nocturnal BP drop, and suppress or eliminate morning BP spikes.

However, bedtime administration may be associated with significant risks, such as a sharp drop in blood pressure during nighttime sleep that may lead to cardiovascular complications and can lower treatment compliance.

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One might argue that taking hypertension medication at bedtime is a reasonable approach for people who don’t drink alcohol, or who suffer from nighttime high blood pressure alone or high morning blood pressure. To date, the supporting evidence, clinical relevance, and indications for bedtime medication remain controversial.

For example, in 2017, the American Diabetes Association recommended taking one or more blood pressure medications at bedtime. This recommendation has not been endorsed by other organizations or diabetes guidelines, possibly due to the criticism it has received.

On the other hand, a 2019 study by scientists in Spain, published in the European Heart Journal, shows that taking blood pressure medication before bedtime is more protective of cardiovascular outcomes than regular morning administration. As these findings have not been confirmed by other investigators, the methods, results, and conclusions of these studies have been questioned. However, the data has drawn a lot of media attention and influenced some specialists, practitioners, and patients.

What Is Nocturnal Hypertension?

Usually, blood pressure is relatively high in the morning, peaks around midday, and drops in the evening; blood pressure is usually higher during the day and lower at night.

For a healthy person, morning blood pressure is less than 130/80 mm Hg, and nighttime blood pressure is less than 110/65 mm Hg. When nighttime blood pressure decreases by 10 percent to 20 percent of an individual’s daytime blood pressure, it is considered a normal decline; a higher or lower dip is not a good sign.

Nocturnal hypertension is when nighttime blood pressure is higher than 110/65 mm Hg. Nocturnal hypertension is often masked because nocturnal blood pressure changes may not receive sufficient monitoring and attention.

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In both hypertensive patients and the general population, nocturnal hypertension and unreduced blood pressure are associated with an increased risk of organ damage and adverse cardiovascular and renal outcomes. People with diabetes seem to be more prone to autonomic dysfunction, and the higher the nighttime blood pressure, the higher the risk of diabetic nephropathy.

A large proportion of patients with nocturnal hypertension have intractable hypertension, in which the nocturnal drop in blood pressure is not significant. These hypertension patients are usually associated with sympathetic nervous system overactivity, obesity, salt retention, and aldosteronism (adrenal gland overproduction of the hormone aldosterone).

The traditional view recommends the application of hypertension drugs upon waking up in the morning, because this may better control the peaks of fluctuations in blood pressure. However, recent studies have shown that oral antihypertensive drugs at night may bring more benefits—especially the Hygia Chronotherapy Trial, which has pushed this debate to a climax.

The Hygia Chronotherapy Trial, published in 2019, is a controlled prospective trial that investigated 19,084 hypertension patients whose mean age was 60.5 years. They were divided into two groups, the similarity being that they were all taking at least one antihypertensive drug. The difference between the groups was the time at which they took the antihypertensive: One group took it at night before bedtime and the other group took it in the morning upon waking.

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During more than six years of follow-up, 1,752 patients developed at least one adverse cardiovascular disease—for example, myocardial infarction or stroke.

The trial results show that patients who took the drug at night had a 45 percent lower risk of a major cardiovascular event, a 49 percent lower risk of stroke, a 34 percent lower risk of myocardial infarction, and a 40 percent lower risk of coronary revascularization. The risk of heart failure was reduced by 42 percent and the risk of cardiovascular death was reduced by 56 percent.

The publication of the Hygia findings sparked widespread discussion, with Blood Pressure, a journal of the European Society of Hypertension, quickly publishing an editorial refuting the findings of the Hygia study.

It began with critiquing the methodology of the study: “There is no evidence that the strict rules that apply to RCTs were implemented, no indication of how the conduct of the study was monitored and no documentation of the membership of the event adjudication committee or of audit by independent investigators.”

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It also cast doubt on whether it was technically possible to measure what the Hygia study claimed to measure: “Ambulatory blood pressure measurements (ABPM) were made with Spacelabs instruments that barely last 48 h in clinical use even when rechargeable batteries were used. Performing 48 h measurements on more than 19,000 patients annually would result in an enormous battery consumption. At last, in total, the HYGIA study should have produced over 150,000 long-term blood pressure measurements with a failure rate of less than 10% – which we cannot achieve in clinical use – not even with Spacelabs devices.”

The board advised more than caution, it wrote that “we must disregard” the Hygia data completely, warning of dangers for patients who experience blood pressure in the middle of the night.

The TIME study, published at the European Society of Cardiology (ESC) Congress 2022, also refuted the Hygia study. TIME is a large prospective randomized trial designed to test whether evening antihypertensive dosing improves major cardiovascular outcomes compared with morning dosing. The study, one of the largest cardiovascular studies ever conducted, provides further answers on whether blood pressure medication should be taken in the morning or evening.

“The risk of heart attack, stroke, and vascular death appears to be similar regardless of the timing of the antihypertensive medication. Hypertensive patients can choose the timing of taking antihypertensive drugs according to their personal habits,” said lead researcher Professor Thomas MacDonald, of the University of Dundee, UK

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Judging from these studies, it may be too early to conclude the best treatment time for hypertension. The question of whether nighttime dosing might be more beneficial than morning dosing is nuanced and far from settled.

Who Should Take Antihypertensive Drugs Before Going to Bed?

Cardiovascular outcomes are affected by circadian blood pressure patterns in hypertension patients, and assessment of these patterns using 24-hour BP monitoring improves outcomes. In fact, the time of antihypertensive drug administration should be formulated according to individual blood pressure classification:

1) For non-dippers (nocturnal blood pressure decreases by less than 10 percent of daytime blood pressure) and reverse dippers (nocturnal blood pressure higher than daytime blood pressure), evening dosing can be used to adjust blood pressure. This dosing method has potential cardiovascular and cerebrovascular benefits.

2) For extreme dippers (nocturnal blood pressure decreases by more than 20% of daytime blood pressure), since the risk of an excessive drop in nighttime blood pressure cannot be readily assessed, it is prudent to take it in the morning.

What is dipper blood pressure? At this stage, the following algorithm is used: (daytime blood pressure – nighttime blood pressure)/daytime blood pressure x 100, and this number is taken as a percentage.

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If this value is between 10 and 20 percent, it is dipper blood pressure; this is a normal blood pressure rhythm.

The following three are abnormal blood pressure rhythms, all of which are harmful to the body:

• If this value is > 20%, it is extreme dipper blood pressure.
• If this value is < 10%, it is non-dipper blood pressure.
• If nighttime blood pressure is higher than daytime blood pressure, it is reverse dipper blood pressure.

Natural Ways to Avoid Nighttime Hypertension

Maintain a regular schedule for work and rest, make sure you get enough sleep, prevent overexcitement, and avoid drinking strong tea or coffee before bed. A hot bath can help you sleep better and lower blood pressure at night. At least 30 minutes before bedtime, shut off the electronics.

Some studies suggest that taking a certain dose of melatonin will help with nocturnal hypertension. Healthy people secrete high amounts of melatonin at night, but patients with nocturnal hypertension tend to secrete less.

A 2014 study published by the Archives of Medical Science shows that more than 30% of non-dippers with diabetes restored their normal circadian rhythm of blood pressure after they took melatonin; both the 3 mg and 5 mg doses administered had significant effects.

As the issue of melatonin overdosing is of concern, ask your doctor if you can lower your blood pressure at night by taking melatonin, and what the ideal dosage is. However, patients with several common disorders—for instance, an autoimmune condition—might not be able to lower blood pressure by regulating melatonin.