1. Home
  2. Time and Motion Studies

Time and Motion Studies

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

Author/s: 
Mackenzie, I. S., Rogers, A., Poulter, N. R., Williams, B., Brown, M. J., Webb, D. J., Ford, I., Rorie, D. A., Guthrie, G., Grieve, J. W. K., Pigazzani, F., Rothwell, P. M., Young, R., McConnachie, A., Struthers, A. D., Lang, C. C., MacDonald, T. M.

Background: Studies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening (TIME) study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension.

Methods: The TIME study is 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. Endpoints were identified by participant report or record linkage to National Health Service datasets and were adjudicated by a committee masked to treatment allocation. The primary endpoint was assessed as the time to first occurrence of an event in the intention-to-treat population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants who submitted at least one follow-up questionnaire. The study is registered with EudraCT (2011-001968-21) and ISRCTN (18157641), and is now complete.

Findings: Between Dec 17, 2011, and June 5, 2018, 24 610 individuals were screened and 21 104 were randomly assigned to evening (n=10 503) or morning (n=10 601) dosing groups. Mean age at study entry was 65·1 years (SD 9·3); 12 136 (57·5%) participants were men; 8968 (42·5%) were women; 19 101 (90·5%) were White; 98 (0·5%) were Black, African, Caribbean, or Black British (ethnicity was not reported by 1637 [7·8%] participants); and 2725 (13·0%) had a previous cardiovascular disease. By the end of study follow-up (March 31, 2021), median follow-up was 5·2 years (IQR 4·9-5·7), and 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. A primary endpoint event occurred in 362 (3·4%) participants assigned to evening treatment (0·69 events [95% CI 0·62-0·76] per 100 patient-years) and 390 (3·7%) assigned to morning treatment (0·72 events [95% CI 0·65-0·79] per 100 patient-years; unadjusted hazard ratio 0·95 [95% CI 0·83-1·10]; p=0·53). No safety concerns were identified.

Interpretation: 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.

Funding: British Heart Foundation.

Keywords 
Intention to Treat Analysis Antihypertensive Agents Cardiovascular Diseases Surveys and Questionnaires United Kingdom

Physical Therapy Versus Glucocorticoid Injection for Osteoarthritis of the Knee

Author/s: 
Deyle, GD, Allen, CS, Allison, SC, Gill, NW, Hando, BR, Petersen, EJ, Dusenberry, DI, Rhon, DI

Background: Both physical therapy and intraarticular injections of glucocorticoids have been shown to confer clinical benefit with respect to osteoarthritis of the knee. Whether the short-term and long-term effectiveness for relieving pain and improving physical function differ between these two therapies is uncertain.

Methods: We conducted a randomized trial to compare physical therapy with glucocorticoid injection in the primary care setting in the U.S. Military Health System. Patients with osteoarthritis in one or both knees were randomly assigned in a 1:1 ratio to receive a glucocorticoid injection or to undergo physical therapy. The primary outcome was the total score on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 1 year (scores range from 0 to 240, with higher scores indicating worse pain, function, and stiffness). The secondary outcomes were the time needed to complete the Alternate Step Test, the time needed to complete the Timed Up and Go test, and the score on the Global Rating of Change scale, all assessed at 1 year.

Results: We enrolled 156 patients with a mean age of 56 years; 78 patients were assigned to each group. Baseline characteristics, including severity of pain and level of disability, were similar in the two groups. The mean (±SD) baseline WOMAC scores were 108.8±47.1 in the glucocorticoid injection group and 107.1±42.4 in the physical therapy group. At 1 year, the mean scores were 55.8±53.8 and 37.0±30.7, respectively (mean between-group difference, 18.8 points; 95% confidence interval, 5.0 to 32.6), a finding favoring physical therapy. Changes in secondary outcomes were in the same direction as those of the primary outcome. One patient fainted while receiving a glucocorticoid injection.

Conclusions: Patients with osteoarthritis of the knee who underwent physical therapy had less pain and functional disability at 1 year than patients who received an intraarticular glucocorticoid injection. (ClinicalTrials.gov number, NCT01427153.).

Keywords 
physical therapy glucocorticoids knee osteoarthritis
Subscribe to Time and Motion Studies