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

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Article Citation

Hermida R,et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. European Heart Journal.

Clinical Question

In patients with hypertension, does bedtime treatment with one or more hypertension medications (ARB, ACEI, CCB, β-blocker, and/or diuretic) compared to treatment upon awakening improve ambulatory blood pressure (ABP) control and reduce the risk of major cardiovascular events?

Bottom-Line Recommendation

In patients with hypertension, bedtime treatment with one or more hypertension medications (ARB, ACEI, CCB, β-blocker, and/or diuretic) resulted in improved ABP control and a 45% reduction in the primary composite CVD outcome (CVD death, MI, coronary revascularization, heart failure or stroke) compared to treatment upon awakening.

Major Points

The bedtime use of hypertension medication is relevant because the average asleep blood pressure determined by ABP monitoring is a significantly more sensitive prognostic marker of CVD risk, compared to the average awake blood pressure determined by ABP monitoring and office visits. Therefore, average asleep blood pressure carries with it the potential to more accurately assess a patient’s risk of CVD events. This difference stems from the circadian-rhythm’s effect on both the medication itself and mechanisms of blood pressure control, including the renin-angiotensin-aldosterone system. The Hygia Chronotherapy Trial looks at Caucasion Spanish patients with hypertension who are being treated with either an ARB, ACEI, CCB, β-blocker, and/or diuretic at bedtime or upon waking.

This trial follows a multicenter, controlled, prospective endpoint design that analyzed 19,084 hypertension patients, with 9552 assigned to the bedtime treatment regimen and 9532 patients assigned to the morning treatment regimen. After an average follow up of 6.3 years, patients of the bedtime treatment regimen had significantly improved ABP control and consequently a 45% reduction (HR: 0.55) in the primary composite CVD outcome. Analysis of the individual primary outcomes showed significant and similar results. Improvement of ABP was defined by the trial as a significantly enhanced decrease in asleep blood pressure and increased relative blood pressure decline (blood pressure dipping). The results also demonstrated that any safety differences associated with the bedtime regimen versus the morning regimen were not of significance (p = .061). Despite this study lacking a randomized-controlled trial design, the trial had independent and blind adjudication of primary outcome events.

Of the studies published, this trial’s results are in line and consistent with a decreased risk of CVD events in patients who are treated with bedtime hypertension medication versus upon awakening. The trial is also highly useful in clinical practice, as it focuses on the primary care setting. Although this trial had an unequal distribution of patients per class of medication, these medications were equally distributed between the two groups studied. The medication a participant received was based on patient-specific factors/preference, and prescribed to them in the primary care setting, further amplifying its relevance to clinical practice. Despite the advantage of a large sample size, the results are limited to Caucasian Spanish individuals.

Guidelines

There are currently no hypertension guidelines that address or recommend a specific administration time of antihypertensive medications.

Study Design

Trial type: Multicenter, controlled, PROBE (prospective, randomized, open-label, blinded endpoint) N=19,084 patients with hypertension Bedtime Treatment: n = 9552 Morning Treatment: n = 9532 Setting: Network of 40 primary care centers within the Galician Social Security Health Service, Northern Spain Enrollment: 2008-2018 Mean follow-up: 6.3 years Analysis: Intention-to-treat Primary outcome: Composite of CVD death, MI, coronary revascularization, heart failure or stroke

Population

Inclusion criteria

Ability to adhere to a routine of daytime activity and nighttime sleep Diagnosis of hypertension according to the 48 hour ABP criteria completed at baseline Awake systolic BP mean ≥135 mmHg, awake diastolic BP mean ≥85 mmHg Asleep systolic BP mean ≥120 mmHg, asleep diastolic BP mean ≥70 mmHg Prescription of blood pressure lowering treatment

Exclusion criteria

Pregnancy History of alcoholism or narcotic addiction Night or rotating shift-work employment Acquired immunodeficiency syndrome (AIDS) Secondary hypertension Cardiovascular disease and related medical conditions: unstable angina pectoris, heart failure, life-threatening arrhythmia, atrial fibrillation, kidney failure, and grade III- IV retinopathy Intolerance to ABP monitoring Inability to communicate and comply with all study requirements Inability of completing ≥1 year minimal follow-up

Baseline characteristics of the study population

For the bedtime regimen treatment group: Demographics: Average age of 60.6, male 55% PMH 

Type 2 diabetes (24.1%)
Obstructive sleep apnea (3.9%)

Smoking (14.8%) Obesity (43.5%) Chronic kidney disease (28.9%) Previous CVD events (10%) Hypertension Treatment Prior to Enrollment: 56.9% Duration of Known Hypertension: 8.8 years Enrollment Health Data (Office Visit BP and ABP, mmHg): Office SBP 149.5, office DBP 86 Awake SBP mean 135.9, awake DBP mean 81.3 Asleep SBP mean 123.7, asleep DBP mean 70.3 48H SBP mean 131.7, 48H DBP mean 77.5 Sleep Time Blood Pressure Declines Relative SBP decline 9% Relative DBP decline 13.2% Non-dipper 49.5% No clinically significant between-group differences were reported within the population at baseline.

Intervention

Following a PROBE design, this study followed patients that were prescribed either an ARB, ACEI, CCB, β-blocker, and/or diuretic and randomized to take the medication at bedtime or upon awakening. The medications were dosed according to current practice guidelines, with each patient taking one of those specific medications at the appropriate dose prescribed to them.

Outcomes (Primary, Secondary, Subgroup, Adverse Events)

Primary Outcomes:Composite of CVD death, MI, coronary revascularization, heart failure or stroke

Patients of the bedtime treatment regimen group had a significantly lower hazard ratio of the primary CVD outcome compared to the morning treatment regimen [HR = 0.55, (95% CI 0.50-0.61), P < 0.001].

Secondary Outcomes

Patients of the bedtime treatment regimen group also had a significant risk reduction for the secondary endpoints of: _ stroke [0.51 (0.41 - 0.63), P <0.001] coronary events [0.56 (0.49 - 0.64), P<0.001] cardiac events [0.57 (0.51- 0.63, P <0.001] minor events 0.60 [0.52-0.69], P<0.001].

Subgroup Analyses

Subgroups that were analyzed during this trial include: Sex Age Smoking status Previous hypertension treatment Baseline ambulatory systolic blood pressure Complications influencing diabetes, cardiovascular disease, and/or previous cardiovascular events.

Adverse Events

This study did not focus on the adverse events both treatment groups experienced, however noted that there was no significant difference in safety between both the bedtime treatment group and morning treatment group.

Criticisms

Internal criticisms

The study only followed Caucasian Spanish individuals, limiting its applicability to other ethnic groups. The trial did not assign participants to specific hypertension medication classes or to a specific list of medications in a class. There were unbalanced numbers of patients in individual medication classes. The study lacked the traditional double-blind, randomized-controlled trial (RCT) design.

External criticisms

A thorough review of current literature revealed a limited number of external criticisms of the Hygia Chronotherapy Trial. This is due in large part to the rigorous design of this trial, including a large sample size (n = 19084), robust length of follow-up (median 6.3 year follow-up), and highly statistically significant outcomes as evidenced by powerful hazard ratios (HR = 0.55, p < 0.001). Further, as a result of the October 2019 publication date, there is a limited amount of time for external criticisms or confirmatory trials to be published. These external criticisms include: Open-label trial design External bias was introduced into the trial design because the primary CVD endpoint contained mostly nonfatal outcomes, which could have been subjectively uncovered by investigators Use of COX model to interpret results, not standard practice for randomized-controlled trials

Funding

Study supported by unrestricted grants from 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 (AtlantTIC); Vicerrectorado de Investigación, University of Vigo.

References

Written by J William McEvoy MB BCh BAO. 2019 Top Stories in Cardiology: The Hygia Chronotherapy Trial [Internet]. PracticeUpdate. Elsevier; 2019 [cited 2020April12]. Available from: https://www.practiceupdate.com/content/2019-top-stories-in-cardiology-the-hygia-chronotherapy-trial/93679

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