Not only does taking antihypertensive drug at bedtime lead to better control of blood pressure (BP), it nearly halves the risk of cardiovascular events compared with dosing upon waking, according to the Hygia Chronotherapy Trial — thus debunking the long-held belief that antihypertensives should be taken in the morning.
"Current guidelines on the treatment of hypertension do not mention or recommend any preferred treatment time. Morning ingestion has been the most common recommendation by physicians based on the misleading goal of reducing morning BP levels," said lead author Professor Ramón Hermida of University of Vigo in Vigo, Spain.
"Furthermore, there are no studies showing that treating hypertension in the morning improves the reduction in the risk of CVD," he added.
Bedtime the best time?
During a median follow-up of 6.3 years, hypertensive patients who took their medications at bedtime were 45 percent less likely than those medicating upon waking to develop the primary composite cardiovascular disease (CVD) outcome (adjusted hazard ratio [HR], 0.55; p<0.001). [Eur Heart J 2019;doi:10.1093/eurheartj/ehz754]
Bedtime dosing also led to significantly lower risk of each of the single components of the primary endpoint, namely myocardial infarction (HR, 0.66), heart failure (HR, 0.58), stroke (HR, 0.51), coronary revascularization (HR, 0.60), and CVD death (HR, 0.44; p<0.001 for all).
Moreover, the above findings remained even after adjusting for multiple variables including age, sex, asleep systolic BP (SBP), sleep-time relative SBP decline, type 2 diabetes, HDL cholesterol, chronic kidney disease, smoking, and previous CVD event.
"The Hygia Project has reported previously that average SBP when a person is asleep is the most significant and independent indication of CVD risk, regardless of BP measurements taken while awake or when visiting a doctor," said Hermida.
In keeping with this, the researchers found that both asleep SBP and diastolic BP (DBP) were significantly lowered in the bedtime dosing group compared with the upon-waking group (p<0.001 for both).
Importantly, the lower asleep BP was achieved without loss of efficacy in lowering awake BP. Office BP was significantly lower with bedtime dosing, regardless of whether it was for systolic or diastolic (p<0.001 for both).
"Indeed, progressive decrease in the asleep SBP mean during the 6.3 years of follow-up was the most significant predictor of reduced CVD risk, beyond the prognostic value of other associated conventional risk markers," stated Hermida and co-authors.
Effects on other CVD markers
Hygia was a large prospective multicentre trial with a PROBE* design, which randomized 19,084 hypertensive patients (mean age 60.5 years, 55.6 percent male) in a 1:1 ratio to take their entire daily dose of hypertension medications at bedtime or upon awakening. The participants were monitored on ambulatory blood pressure (ABP) performed over 48 hours at baseline and at each scheduled clinic visit during follow-up.
By the end of the study, taking antihypertensives at bedtime led to more favourable lipid profile, as indicated by lower LDL cholesterol (mean, 118.2 vs 120.7 mg/dL; p=0.002) and higher HDL cholesterol levels (mean, 53.0 vs 51.8 mg/dL; p<0.001) vs dosing upon waking.
Similarly, renal function was also significantly improved with bedtime vs upon-waking dosing — as reflected by higher eGFR** (mean, 79.3 vs 75.7 mL/min/1.73 m2; p<0.001) and lower serum creatinine (mean, 1.06 vs 1.16 mg/dL; p<0.001) and albumin/creatinine ratio (median, 6.5 vs 7.0; p=0.03).
All of the above measures, the researchers pointed out, are well-recognized relevant biomarkers of CVD risk.
There were no differences in the rates of patient-reported adverse effects. In particular, no increase in hypotension was seen, as was its potential sequelae such as falls.
Take-away from the study
"In keeping with previous findings, [our] results document that bedtime hypertension therapy is at least as safe, and with similar patient compliance and adherence, than usual upon-waking therapy," said the researchers.
Nonetheless, there are considerations that needed to be taken into account with respect to the drug's mechanism of action.
"Many antihypertensive drugs, particularly diuretics, may not be tolerated when given at bedtime. Indeed, diuretics were used somewhat less frequently in the bedtime administration group," wrote the editorialists led by Dr Jawahar Mehta from the University of Arkansas for Medical Sciences in Little Rock, Arkansas, US in an accompanying editorial. [Eur Heart J2019;doi:10.1093/eurheartj/ehz836]
"[The current findings] and those previously reported from the Hygia Project indicate that [the] average BP levels while asleep and nighttime BP dipping, but not daytime BP or BP measured in the clinic, are jointly the most significant BP-derived markers of CV risk," said Hermida. "Accordingly, round-the-clock ABP monitoring should be the recommended way to diagnose true arterial hypertension and to assess the risk of CVD."
[MIMS Feb. 2020]