Optimal Time to Administer Once-Daily Oral Cardiovascular Agents: Evidence Based on Randomized Clinical Trials in the Last Ten Years

Background: Sporadic studies have investigated the influence of administration time (morning versus evening) on the efficacy and safety of once-daily medications. It is necessary to let clinicians know the developments during the last ten years. Methods: Focusing on chronotherapeutic topic, a literature search on randomized controlled trials (RCTs) of oral oncedaily cardiovascular agents was conducted using PubMed, Cochrane Library, Scopus and Web of Science from Jan 01, 2008 to Sept 30, 2018. Results: Forty-seven RCTs investigated cardiovascular agents. Thirty-five RCTs showed the advantages of evening or bedtime dosing, only one RCT showed the superiority of morning dosing (perindopril for patients with obstructive sleep apnoea and hypertension), and 11 RCTs showed no relationship between dosing time and therapeutic outcomes. Two RCTs reported the difference in occurrence of actual side effects following morning versus evening administration (significantly lower incidence of edema following bedtime dosing of nifedipine rather than morning dosing, significantly lower rate of CKD event following bedtime dosing of ≥ 1 hypertension medications rather than therapy with all medications upon awakening). Rivaroxaban and amlodipine were cases of exhibiting chronopharmacokinetic feature. Factors determining whether to exhibit administration timedependent effects may include disease characteristics, gender, drug combination, treatment course, types of medications, dose, pharmaceutical dosage forms, and outcome measures. Conclusion: Chronotherapy intervention may be considered to improve medication therapy management before attempting to increase dose or add more drugs. Clinicians should educate patients about optimal administration time to take oral oncedaily medications. More RCTs are needed to explore the possibility of optimal dosing time because relevant descriptions are unavailable in prescribing information for many once-daily oral cardiovascular medications.