Blood Pressure Medications: A Bedtime Story

June 12, 2023

By Jonah Klapholz                                                            

Peer Reviewed

Telling patients to take their blood pressure medications at night is a common practice for many clinicians. Yet, this strategy—labeled “chronotherapy” by its proponents—is controversial. It has been debated in the decades since captopril, the snake venom-derived first angiotensin-converting enzyme (ACE) inhibitor, was offered to patients in 1981. Multiple studies have sought to clarify the best time of day to take ACE inhibitors and their sleeker younger counterparts, the angiotensin receptor blockers (ARBs). New data emerged in 2022 that may settle the debate once and for all.

But why does this matter? Why has there been so much research on the seemingly simple issue of time of day, especially when it has no impact on the cost of care? First, hypertension is prevalent, affecting roughly 116 million people—about one-third of the population—in the US alone. It is estimated that 91.7 million of those people qualify for medication with antihypertensives, drugs that have undisputed mortality benefits when it comes to cardiovascular disease and end-organ damage.1

In 1988, a small abstract by Eoin O’Brien, James Sheridan, and Kevin O’Malley appeared in the Lancet and described “dippers and non-dippers,” differentiating between individuals whose blood pressures fluctuate diurnally and individuals whose pressures do not. In a small study comprising 123 patients, “dippers” saw a nocturnal drop in systolic and diastolic blood pressures of 10 and 5 mmHg, respectively. In contrast, “non-dippers,” even if they were normotensive, saw no such drop.2 The authors’ speculation that “non-dippers” might be at higher risk of hypertension-related end-organ dysfunction, cardiovascular disease, and mortality was confirmed in multiple studies in the ensuing decades. The first was a Japanese study conducted from 1991 to 2002 that followed 1542 patients with at-home blood pressure measurements and showed a significant positive association between the absence of nocturnal blood pressure decline and cardiovascular mortality, even when 24-hour blood pressures were in the normal range.3

Multiple studies in Europe and the US produced similar results.4,5,6 In the wake of findings demonstrating that nighttime blood pressure is a better predictor of mortality than daytime pressure, a new clinical practice emerged. By giving antihypertensives at night, clinicians could turn all their patients into “dippers,” potentially providing a mortality benefit.6 Yet, in the early 2000s, very little data confirmed this in practice. The mortality benefits of ACE inhibitors and ARBs were well established, but no large-scale trial existed confirming an added benefit of administering them at nighttime.

The MAPEC (Monitorización Ambulatoria de la Presión Arterial y Eventos Cardiovasculares) study was the first randomized controlled trial to assess the potential benefit of chronotherapy. Conducted in Spain, the trial randomized 2156 patients with untreated or treatment-refractory hypertension into morning and night medication groups. Participants were followed for a median of 5.6 years and were instructed to wear an at-home blood pressure cuff for 48 hours, which would take measurements automatically every 20 minutes, at least once per year. Patients in the nighttime arm not only exhibited “dipper” physiology more frequently but also had a significantly lower incidence of cardiovascular events (11.95 vs. 27.8 events per 1,000 patient years p < 0.001, NNT= 63). An effect on all-cause mortality was also noted, albeit more modest (2.11 vs. 4.16 events per 1,000 patient-years, p = 0.008, NNT =  488).7

To that end, the MAPEC trial was a success at first glance. But the study was not a slam dunk in favor of chronotherapy. Critics were quick to point out MAPEC’s flaws: that the trial was open-label and single-center, and that the type and amount of antihypertensives given was left entirely up to individual providers.

The research group responsible for the MAPEC trial went at it again, employing a fundamental tenet of clinical research—bigger is better. The result was the Hygia Chronotherapy trial, structurally similar to MAPEC but conducted with 19,168 patients across 40 centers. Participants were allocated to administer all blood pressure medications at night or in the morning and were followed for a median of 6.3 years. Like MAPEC, they were instructed to wear an automatic cuff for 48 hours at least once per year. In 2020, the study concluded that bedtime dosing of antihypertensives was associated with a 5.4% risk reduction in a composite cardiovascular outcome consisting of death, myocardial infarction, heart failure, and stroke (hazard ratio = 0.55).8

At face value, the results of Hygia lent external validity to MAPEC, proving what some clinicians already thought to be self-evident since the early 2000s. But the trial was controversial and became embroiled in accusations of data misrepresentation and ethical misconduct. Issues cited included poor oversight of interim analyses while the study was ongoing and a lack of clarity regarding stopping criteria were the trial to show a clear benefit before its scheduled conclusion. Improper randomization of participants based on the type of medication received was also a significant concern. Moreover, critics pointed out that the demonstrated benefit of chronotherapy on non-cardiovascular mortality, based on the results reported in Hygia, can be calculated as roughly 40%, a number that lacks explanation and is just too good to be true without bias at play. Hygia’s significant conclusion as to the benefits of chronotherapy in the context of improper data management, ethical concerns, and identifiable bias led to accusations of fraud. The problems were clear, credible, and big enough for the European Heart Journal to conduct an internal investigation, none of which has been made public.9,10

In October 2022, chronotherapy took an evidence-based blow when the results of the TIME (Treatment in Morning versus Evening) trial were published. Conducted in the UK, TIME was an open-label, multi-center, blinded-endpoint trial that randomized 21,104 patients taking at least one blood pressure medicine into morning and nighttime groups. Participants were followed for a median of 5.2 years and were instructed to log at-home morning and nighttime blood pressures at 3-month intervals. The trial’s composite endpoints were similar to those of its predecessors—nonfatal and fatal cardiovascular events, and all-cause mortality. But the results stood in stark contrast to Hygia. Cardiovascular death, myocardial infarction, or stroke occurred in 3.4% of the nighttime group and 3.7% of the morning group (p = 0.53). While systolic blood pressure measured in the morning was higher in the morning group, reflecting the ability of antihypertensives to facilitate “dipper” physiology, there was no cardiovascular or all-cause mortality benefit with taking blood pressure medications at night. The study thus concluded that patients could take antihypertensives in the morning or at night, according to what they prefer.11

The principal investigator of the TIME trial, Thomas MacDonald of the University of Dundee, UK, said, “TIME was one of the largest cardiovascular studies ever conducted and provides a definitive answer on the question of whether blood pressure lowering medications should be taken in the morning or evening.”12 His confidence notwithstanding, the study has drawbacks, including that much of it was conducted during COVID-19. Yet, the TIME trial has many clear advantages over its predecessor. It employed a large, decentralized sample size, used transparent data collection, and randomized patients appropriately. Participants were reminded to do blood pressure checks by automated emails. It had the benefit of using an online portal where patients and their clinicians could log blood pressures, periods of non-adherence, adverse events, and endpoints as they occurred. The conclusions of the study, while still controversial in themselves, are well-founded and have not instigated the pile-on that Hygia received.

Does the TIME trial settle the debate? It might for some. But many clinicians will likely continue to instruct patients to take their blood pressure medications at night either by force of habit or by guidelines based on older trials. While TIME illuminates clear noninferiority of daytime dosing, chronotherapy is still widespread in clinical practice—and it does not cost a dime.

Jonah Klapholz is a 3rd year medical student at NYU Grossman School of Medicine

Peer reviewed by Michael Tanner, MD, associate editor, Clinical Correlations

Image courtesy of Wikimedia Commons, source: Norvasc Amlodipine.jpg


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