Improved reduction of cardiovascular risk by bedtime ingestion of ARB and ACEI medication class therapies

This commentary refers to ‘Chrono-pharmacological effects of antihypertensive drugs’, by S. Şen et al., on page 1601. We appreciate the commentary by Şen et al.1 As stated,2 consistent with the design of the Hygia Chronotherapy Trial (HCT), there were no statistically significant differences at baseline between the two balanced treatment-time groups in any tested variable listed in Table 1. Correcting for multiple testing, we used a P-value of 0.0013, rather than 0.05, to explore significant disparities between treatment-time groups. Additionally, results depicted in Figure 2 of the HCT publication2 were adjusted for all significant influential characteristics associated with increased cardiovascular disease (CVD) risk, including previous occurrence of such events. Finally, unstable angina pectoris, heart failure, life-threatening arrhythmia, and atrial fibrillation were among the listed exclusion criteria.2 The HCT publication also states ‘the number of prescribed hypertension medications was significantly (P < 0.001) lower in the bedtime-treatment regimen, resulting in relatively small differences between groups in the percentage of individuals treated with any given class of single or combination therapy’.2 Accordingly, differences in the proportion of participants treated with some medication classes, including ß-blockers and diuretics—both used mostly as a constituent of combination therapy—were expected, but they did not influence main conclusions. Reported trials on the tested ß-blockers carvedilol and nebivolol, loop-diuretic torasemide, and fixed combinations of captopril/hydrochlorothiazide (HCTZ), valsartan/HCTZ, and amlodipine/HCTZ consistently document greater asleep blood pressure (BP) mean reduction by bedtime than upon-waking therapy scheduling.3 We further evaluated the impact of hypertension treatment-time on CVD-outcome according to BP-lowering medication class. The Figure shows better CVD-outcome risk reduction for bedtime vs. awakening treatment for every one of the five classes of BP-lowering medication. Adjusted hazard ratio of CVD-outcome was equivalent across all five medication classes when ingested upon awakening, but it was significantly lower when either an ARB or ACEI was ingested at bedtime compared to any other medication class ingested either at bedtime or upon awakening (Figure 1). Improved benefits—enhanced asleep BP reduction and diminished CVD risk—result from blocking/modulating the usual sleep-time activation of the renin–angiotensin–aldosterone system by ARB/ACEI bedtime chronotherapy, as previously reported.4 Findings depicted in the Figure, however, should be taken with caution because contrary to the MAPEC study in which patients were independently randomized to each of the reduced list of allowed BP-lowering medications for first-line treatment,4 HCT participants were randomized only to treatment-time, but not medication-class.2 Adjusted hazard ratio (95% confidence interval) of cardiovascular disease-outcome as a function of medication-class and hypertension treatment-time regimen (either upon awakening or at bedtime) referenced to ARB ingested at bedtime. Conflict of interest: none declared.