Bedtime Hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial

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Ramón C Hermida, Juan J Crespo, Manuel Domínguez-Sardiña, Alfonso Otero, Ana Moyá, María T Ríos, Elvira Sineiro, María C Castiñeira, Pedro A Callejas, Lorenzo Pousa, José L Salgado, Carmen Durán, Juan J Sánchez, José R Fernández, Artemio Mojón, Diana E Ayala, Hygia Project Investigators, Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial, European Heart Journal, ehz754, https://doi.org/10.1093/eurheartj/ehz754


Clinical Question


In a patient with cardiovascular disease, does bedtime hypertension treatment improve cardiovascular risk reduction compared to normal treatment when waking up?


Bottom-line Recommendation


“Routine ingestion by hypertensive patients of ≥1 prescribed BP-lowering medications at bedtime, as opposed to upon waking, results in improved prevention of adverse CVD events”.


Major Points


  • The Hygia Chronotherapy Trial, conducted within the clinical primary care setting, was designed to test whether bedtime in comparison to usual upon awakening hypertension therapy exerts better cardiovascular disease (CVD) risk reduction.
  • The population studied included patients at risk of CVD events with current diagnosis of hypertension according to ABPM criteria (ambulatory blood pressure monitoring).
  • Such administration-time differences in the effects of BP-lowering medications arise from circadian rhythm-dependent influences both on their pharmacokinetics and pharmacodynamics as well as on the mechanisms of BP regulation.
  • For example, peak activity of the renin–angiotensin–aldosterone system (RAAS) occurs during sleep. Accordingly, bedtime in comparison to upon-waking ingestion of once-a-day formulations of angiotensin-II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs)—as well as their tested combinations with calcium channel blockers (CCBs) and diuretics—results in considerably enhanced reduction in asleep BP mean without compromised therapeutic effect on awake BP.
  • These findings are important as they could mean a change towards current guidelines: the inclusion of BP medications to be taken at bedtime instead of in the morning upon awakening.
  • Current guidelines such as ESC and AHA don’t currently have time-of-day administration listed in their recommendations, but most common practice uses morning administration of BP medications.


Guidelines


  • ESC/EHS Guidelines for the management of arterial hypertension
  • Five major drug classes were recommended for the treatment of hypertension: ACE inhibitors, ARBs, beta-blockers, CCBs, and diuretics

(No current recommendation for time of day administration)

  • AHA Guidelines:
  • The updated guideline presents new treatment recommendations, which include lifestyle changes as well as BP-lowering medications (from the 5 major drug classes for hypertension)


Study Design


This trial was designed by using PROBE guidelines (prospective, randomized, open-label, blinded endpoint) where patients were distributed in a 1:1 ratio defined by what time of day each intervention was; either an entire daily dose of ≥1 prescribed BP-lowering medications of the major therapeutic classes (ARB, ACEI, CCB, β-blocker, and/or diuretic) at bedtime (bedtime-treatment regimen; n = 9552) or ingestion of all of such medications upon awakening (awakening-treatment regimen; n = 9532;).


Population (inclusion, exclusion, baseline demographics)


  • Number of medications 1.8 +/- 0.89 in waking patients and 1.71+/- 0.93 in bed time patients with p < 0.001

ARB

53.1% of Waking Patients
53.1% of Bedtime Patients
P value = 0.995

ACEI

25.3% of Waking Patients
23.4% of Bedtime Patients
P value = 0.002

CCB

32.7% of Waking Patients
36.8% of Bedtime Patients
P value = 0.001

Beta Blockers

22.0% of Waking Patients
17.5% of Bedtime Patients
P value = 0.001

Diuretics

47.5% of Waking Patients
39.5% of Bedtime Patients
P value = 0.001


  • Participants of the Hygia Chronotherapy Trial represented a population of Caucasian Spanish men and women aged ≥18 years who provided written informed consent for inclusion
  • Population for the hypothesis assessed herein is 19 084 (10 614 men/8470 women) hypertensive patients aged 60.5 ± 13.7
  • Inclusion criteria:
  • adhere to a routine of daytime activity and nighttime sleep.
  • participants were required to have a diagnosis of hypertension according to the Ambulatory blood pressure (ABP) criteria
  • 24-h average → >130/80 mm Hg
  • Awake daytime average → >135/85
  • Asleep night time average → >120/70 mm Gg
  • Exclusion criteria:
  • pregnancy
  • history of alcoholism or narcotic addiction
  • night or rotating shift-work employment
  • acquired immunodeficiency syndrome
  • secondary hypertension
  • CVD and certain associated medical conditions (unstable angina pectoris, heart failure, life-threatening arrhythmia, atrial fibrillation, kidney failure, and grade III–IV retinopathy),
  • intolerance to ABPM
  • inability to communicate and comply with all study requirements
  • The minimum targeted median follow-up was 5 years, with a required ≥1-year minimal follow-up per participant.


Intervention(s)


Participants were instructed to take their prescribed antihypertensive(ARB, ACEI, CCB, B-Blocker, and/or diuretic) regimen (which was prescribed w/ only limitation being that it come from 5 classes that are 1st line for HTN) at either bedtime (n=9552) or upon awakening (n=9532). Single tablet, combo medications were used to improve adherence if needed, and patients were reminded daily to take their mediation at the designated time.


Outcomes (Primary, Secondary, subgroup, adverse events)


  • At the conclusion of the study, the number of prescribed HTN medications in the bedtime group was slightly but significantly lower than that of the daytime group.
  • Primary CVD Outcomes: Patients in the bedtime group had a lower incidence of the main CVD outcomes: “CVD death [HR = 0.44 (0.34–0.56), P < 0.001], haemorrhagic stroke [0.39 (0.23–0.65), P < 0.001], heart failure [0.58 (0.49–0.70), P < 0.001], and peripheral artery disease [0.52 (0.41–0.67), P < 0.001”
  • There were no treatment-time differences in the prevalence of patients reporting AE at any of the followup times.
  • Poor adherence was noted in both groups: 2.8% (awakening) vs. 2.9% (bedtime)


Criticisms


  • Its findings require validation and extrapolation to other ethnic groups
  • This trial did not assign participants to specific hypertension medication classes or specific list of medications within each class (treatment was chosen by each participating clinician respecting current clinical practice)
  • Resulted in an unbalanced number of patients per medication class


Funding


  • Ministerio de Ciencia e Innovación, Spanish Government
  • Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spanish Government
  • Consellería de Economía e Industria, Dirección Xeral de Investigación e Desenvolvemento, Galician Regional Government
  • Consellería de Cultura, Educación e Ordenación Universitaria, Galician Regional Government
  • European Regional Development Fund (ERDF) and the Galician Regional Government under agreement for funding the Atlantic Research Center for Information and Communication Technologies
  • Vicerrectorado de Investigación, University of Vigo


Further Reading