Bedtime versus morning ingestion of hypertension and cardiovascular (CV) risk

Mean asleep blood pressure (BP) versus other measures of blood pressure

• evidence based on both prospective studies and meta-analyses has demonstrated that mean asleep BP determined by ambulatory BP monitoring (ABPM) is a more sensitive prognostic marker of CVD compared to daytime office BP measurements, ABPM-derived awake mean, or 24h BP mean (1,2,3,4,5)
  • shown that therapeutically induced reduction of asleep systolic BP (SBP) mean and enhancement of sleep-time relative SBP decline towards a normal dipper pattern result in reduced CVD risk (3,5)
  • improved normalization of asleep BP and 24h BP patterning was observed when hypertension medications were ingested at bedtime instead of upon awakening (6)

CVD risk and effect of bedtime hypertension medication ingestion:

• MAPEC (Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events) study showed in a small cohort of 2156 hypertensive patients over a median follow-up of 5.6 years that bedtime ingestion of treatment resulted in significantly reduced asleep BP, reduced prevalence of non-dipping, and reduced incidence of CVD events compared to medication intake upon awakening (7)
  • Hermida et al concluded that "..MAPEC study, along with other earlier conducted less refined trials, documents the asleep BP mean is the most significant prognostic marker of CVD morbidity and mortality; moreover, it substantiates attenuation of the asleep BP mean by a bedtime hypertension treatment strategy entailing the entire daily dose of >=1 hypertension medications significantly reduces CVD risk in both general and more vulnerable hypertensive patients, that is, those diagnosed with chronic kidney disease, diabetes and resistant hypertension..."
    
    
• the Hygia Chronotherapy trial is a much larger prospective study of more than 19,000 patients which assessed the effect of timing of ingestion of hypertensive medication on CVD risk (8)
  • a multicenter, controlled, PROBE (prospective, randomized, open-label, blinded endpoint) study with 19084 (10614 men, 8470 women) hypertensive patients aged 60.5 +/- 13.7 (mean +/- SD) years. Patients were randomized to ingest the entire daily dose of >=1 prescribed BP medications of the major therapeutic classes (ARB, ACEI, CCB, beta-blocker, and/or diuretic) at either bedtime (n=9552) or upon awakening (n=9532). ABP was monitored for 48 h at baseline and each clinic visit (at least once a year). The median follow-up was 6.3 years (IQR 4.1-8.3 years)

Main results

• at baseline, 48h SBP of all patients was 131.6 +/- 13.8 mmHg (mean +/- SD) and 48h diastolic BP (DBP) was 77.4 +/- 10.4
  
  
• bedtime-treatment regimen compared to regimen of treatment upon awakening resulted in a significantly lower asleep BP mean (asleep SBP 114.7 +/- 14.6 vs. 118.0 +/- 16.6, and asleep DBP 64.5 +/- 9.3 vs. 66.1 +/- 10.1, respectively, both P<0.001) without loss of awake BP-lowering efficacy
  • larger relative BP decline was observed during sleep in the bedtime-treatment regimen compared to the awakening-treatment regimen (sleep-time relative SBP decline 12.2% +/- 7.7% vs. 8.5% +/- 8.4%, respectively, and sleep-time relative DBP decline 15.3% +/- 8.6% vs. 13.3% +/- 9.4%, respectively, both P <0.001), which led to a significantly lower prevalence of non-dipping (37.5% in the bedtime-treatment regimen vs. 50.3% in the awakening-treatment regimen, P<0.001)
    
    
• patients in the bedtime-treatment regimen had a significantly lower HR of the primary CVD outcome (CVD death, myocardial infarction, coronary revascularization, heart failure, or stroke), compared with patients in the awakening-treatment regimen (HR=0.55 [95% CI 0.50-0.61], P<0.001, adjusted for significant influential characteristics - age, sex, type 2 diabetes, chronic kidney disease, smoking, HDL cholesterol, asleep systolic blood pressure (BP) mean, sleep-time relative systolic BP decline, and previous CVD event-of the primary CVD outcome)
  • numbers of major events were 1133 and 629 for the awakening and bedtime treatment groups, respectively. The NNT is 18.6 95%CI (16.2-22.0) (9)
    
    
• analysis of individual CVD events showed that ingestion at bedtime led to a significant risk reduction compared to ingestion at awakening for CVD death (HR=0.44 [0.34-0.56), P<0.001), hemorrhagic stroke (HR=0.39 [0.23-0.65], P< 0.001), heart failure (HR=0.58 [0.49-0.70], P< 0.001), and peripheral artery disease (HR=0.52 [0.41-0.67], P< 0.001)
  
  
• patients in the bedtime-treatment regimen showed significantly lower creatinine and LDL-c, and higher HDL-c and eGFR compared to patients in the awakening-treatment regimen at the time of the final evaluation
  
  
• no differences in prevalence of adverse effects were found between the bedtime and awakening-treatment regiments (6.0% vs. 6.7% respectively, P=0.061). Prevalence of poor adherence during the follow-up was similar in the bedtime and awakening-treatment regiments (2.9% vs. 2.8% respectively, P=0.813)

The study authors concluded that " Routine ingestion by hypertensive patients of >=1 prescribed BP-lowering medications at bedtime, as opposed to upon waking, results in improved ABP control (significantly enhanced decrease in asleep BP and increased sleep-time relative BP decline, i.e. BP dipping) and, most importantly, markedly diminished occurrence of major CVD events...also demonstrates that the safety of the bedtime hypertension therapeutic scheme is similar to the more common awakening one, a finding consistent with previous publications reporting that bedtime compared with morning BP therapy significantly improves ABP reduction without any increase in adverse effects"

Evening dosing versus morning dosing of blood pressure medication - further evidence (7)

• TIME study
  • a prospective, pragmatic, decentralised, parallel-group study in the UK, that recruited adults (aged >=18 years) with hypertension and taking at least one antihypertensive medication
  • eligible participants were randomly assigned (1:1), without restriction, stratification, or minimisation, to take all of their usual antihypertensive medications in either the morning (0600-1000 h) or in the evening (2000-0000 h)
  • participants were followed up for the composite primary endpoint of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke
  • by the end of study follow-up, median follow-up was 5.2 years
    • 529 (5.0%) of 10,503 participants assigned to evening treatment and 318 (3.0%) of 10,601 assigned to morning treatment had withdrawn from all follow-up
    • primary endpoint event occurred in 362 (3.4%) participants assigned to evening treatment (0.69 events per 100 patient-years) and 390 (3.7%) assigned to morning treatment (0·72 events per 100 patient-years; unadjusted hazard ratio 0.95 [95% CI 0.83-1.10]; p=0.53)
    • no safety concerns were identified
  • study authors concluded:
    • evening dosing of usual antihypertensive medication was not different from morning dosing in terms of major cardiovascular outcomes
    • patients can be advised that they can take their regular antihypertensive medications at a convenient time that minimises any undesirable effects
• a commentary by Professor RC Hermida states (8):
  • "..The TIME trial does not comply with most (7 out of 8) of the main recommendations of the International Society for Chronobiology for the design and conduct of human clinical trials on ingestion-time differences of hypertension medications. In particular, we have the following concerns:
    • Treatment times:
      • Broad clock-time spans (06:00-10:00 vs. 20:00-00:00), unrepresentative of circadian time
    • Patient recruitment:
      • Patient self-recruitment by internet. Prescribing physicians were not investigators and were unaware of treatment-time allocation.
    • Inclusion criteria:
      • Current antihypertensive treatment, based on daytime office BP (leading to inclusion of white-coat hypertension and exclusion of masked hypertension, mainly asleep hypertension)
    • BP status upon recruitment:
      • Most with already controlled daytime office BP (average 135/79 mmHg) (inappropriate, with risk of misleading findings)
    • Follow-up design:
      • Decentralized. Patients contacted only by email, study personnel unknown to them
    • Follow-up BP measurement:
      • None. Only a small proportion (36%) of the patients provided at least one home BP assessment. No other clinically relevant variables were assessed during follow-up
    • Therapeutic recommendations:
      • If nocturia, move evening diuretic ingestion-time first to 18:00h, then morning, compromising assessment of findings and preventing use of single-tablet fixed combinations in the evening treatment group.
    • Therapeutic adjustment during follow-up:
      • Assumingly prescribed if needed, based on daytime office BP, by the patients´ treating physicians, who were not investigators and unaware of treatment-time allocation of their patients. Medications and doses during follow-up, unknown.
    • Adherence assessment:
      • Online questionnaire, only for assigned treatment-time (not medications and doses). Compliance with reporting and recall unknown. Reporting subject to bias.
    • Safety assessment:
      • Patient reporting (compliance unknown) by email. Possible relation to hypertension therapy and dosing-time, unknown. Reporting subject to bias
    • CVD outcome reporting:
      • By patient; linked to anonymized National Health Service records. Reporting subject to bias
    • Drop-outs and protocol violation:
      • 847 patients withdrew full consent, 2453 withdrew from follow-up, 6475 reported non-adherence to dosing time; however, all were included in the analyses
    • Primary outcome comparison:
      • By intention-to-treat, despite known up to 40% non-adherence to allocated (morning vs. evening) dosing time.
    • Reported event-rates for composite outcome of CVD death, MI, and stroke:
      • 3.4% for evening and 3.7% for morning treatment
      • For the same outcome, in the Hygia Chronotherapy Trial:
        • 3.3% for bedtime and 6.5% for upon-awakening treatment
      • In TIME "participants (unreported number) randomly assigned to morning dosing changed to evening dosing in response to high-profile media coverage of the results of the Hygia Chronotherapy Trial"
      • All this suggests the proportion of patients in TIME truly ingesting medications in the evening might have been similar in both treatment-time assigned groups, therefore invalidating the results and conclusions
  • Main conclusion:
    • "Further research is needed to advise on dosing time of BP-lowering medications on patients with nocturnal hypertension or non-dipping". Indeed, elevated asleep SBP mean and non-dipper/riser BP pattern are jointly the strongest and only independent BP-derived predictors of CVD risk, indicating only these patients should be treated..."

Reference:

• Dolan E et al. Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension 2005;46:156-161.
• Boggia J et al. Prognostic accuracy of day versus night ambulatory blood pressure: a cohort study. Lancet 2007;370:1219-1229.
• Hermida RC et al. Decreasing sleep-time blood pressure determined by ambulatory monitoring reduces cardiovascular risk. J Am Coll Cardiol 2011;58:1165-1173.
• Roush GC. Prognostic impact from clinic, daytime, and nighttime systolic blood pressure in 9 cohorts on 13,844 patients with hypertension. J Hypertens 2014;32:2332-2340.
• Hermida RC et al. Asleep blood pressure: significant prognostic marker of vascular risk and therapeutic target for prevention. Eur Heart J 2018;39:4159-4171.
• Hermida RC et al. Chronotherapy with conventional blood pressure medications improves management of hypertension and reduces cardiovascular and stroke risks. Hypertens Res 2016;39:277-292.
• Hermida RC et al Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int 2010;27:1629-1651.
• Hermida RC et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Heart J. 2019 Oct 22
• Personal email communication. Professor RC Hermida (6/11/19).
• Mackenzie IS et al. Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. Lancet. 2022 Oct 11:S0140-6736(22)01786-X.
• Personal email communication. Professor RC Hermida (24/10/22).