Effect of timed dosing of usual antihypertensives according to patient chronotype on cardiovascular outcomes:the Chronotype sub-study cohort of the Treatment in Morning versus Evening (TIME) study

Background: Timing drug administration to endogenous circadian rhythms may enhance treatment efficacy. In the Chronotype sub-study of the Treatment in Morning versus Evening (TIME) clinical trial we examined whether timing of usual antihypertensive medications according to patient chronotype (a behavioural marker of personal circadian rhythm) may influence clinical cardiovascular outcomes.Methods: This was a cohort sub-study of TIME, a prospective, randomised, open-label, blinded-endpoint, UK clinical trial of morning versus evening dosing of usual antihypertensive medications and cardiovascular outcomes. On August 3rd, 2020, all active TIME participants were invited to complete a validated chronotype questionnaire. Chronotype was quantitatively assessed as the mid sleep time on free days corrected for sleep debt on workdays (MSFsc). We analysed associations between chronotype and antihypertensive dosing time and explored their combined effect on cardiovascular outcomes (a composite endpoint of hospitalisation for non-fatal myocardial infarction (MI) or non-fatal stroke, and single components) using proportional hazard time-to-event models adjusted for baseline covariates. These were used to specifically test for interactions between dosing time and chronotype.Findings: Between August 3, 2020, and March 31, 2021, 5358 TIME participants completed the online questionnaire. 2778 were previously randomised to morning dosing and 2580 to evening dosing of their usual antihypertensives. Chronotype was symmetrically distributed around a median MSFsc of 3:07 am. The composite endpoint increased for later MSFsc (later chronotype) dosed in the morning but not in those dosed in the evening (hazard ratios 1.46 [95% CI 1.14-1.86] and 0.96 [95% CI 0.70-1.30] per hour of MSFsc, respectively; interaction p = 0.036). Later chronotype was associated with increased risk of hospitalisation for non-fatal MI in the morning dosing group, and reduced risk in the evening dosing group (hazard ratios 1.62 [95% CI 1.18-2.22] and 0.66 [95% CI 0.44-1.00] per hour of MSFsc, respectively; interaction p &lt; 0.001). No interaction between chronotype and antihypertensive dosing time was observed for stroke events.Interpretation: Alignment of dosing time of usual antihypertensives with personal chronotype could lower the incidence of non-fatal MI compared to a 'misaligned' dosing time regimen. Future studies are warranted to establish whether synchronizing administration time of antihypertensive therapy with individual chronotype reduces risk of MI.</p

Impact of EU regulatory label changes for diclofenac in people with cardiovascular disease in four countries:interrupted time series regression analysis

Objective: Due to cardiovascular safety concerns, the European Medicines Agency (EMA) recommended new contraindications and changes to product information for diclofenac across Europe in 2013. This study aims to measure their impact among targeted populations. Method: Quarterly interrupted time series regression (ITS) analyses of diclofenac initiation among cohorts with contraindications (congestive cardiac failure [CHF], ischaemic heart disease [IHD], peripheral arterial disease [PAD], cerebrovascular disease [CVD]) and cautions (hypertension, hyperlipidaemia, diabetes) from Denmark, the Netherlands, England and Scotland. Results: The regulatory action was associated with significant immediate absolute reductions in diclofenac initiation in all countries for IHD (Denmark −0.08%, 95%CI −0.13, −0.03; England −0.09%, 95%CI −0.13 to −0.06%; the Netherlands −1.84%, 95%CI −2.51 to −1.17%; Scotland −0.34%, 95%CI −0.38 to −0.30%), PAD and hyperlipidaemia, the Netherlands, England and Scotland for hypertension and diabetes, and England and Scotland for CHF and CVD. Post-intervention there was a significant negative trend in diclofenac initiation in the Netherlands for IHD (−0.12%, 95%CI −0.19 to −0.04), PAD (−0.13%, 95%CI −0.22 to −0.05), hypertension, hyperlipidaemia and diabetes, and in Scotland for CHF (−0.01%, 95%CI −0.02 to −0.007%), IHD (−0.017, 95%CI −0.02, −0.01%), PAD and hypertension. In England, diclofenac initiation rates fell less steeply. In Denmark changes were more strongly associated with the earlier EMA 2012 regulatory action. Conclusion: Although significant reductions in diclofenac initiation occurred, patients with contraindications continued to be prescribed diclofenac, the extent of which varied by country and target condition. Understanding reasons for such variation may help to guide the design or dissemination of future safety warnings

Drugs dispensed in primary care during pregnancy:a record-linkage analysis in Tayside, Scotland

Background: For many regularly used drugs, evidence for safe use in pregnancy has not been established. Despite this, international studies have identified high levels of drug prescribing among pregnant women. Objective: To investigate the patterns of prescribing of drugs to women who gave birth in Tayside, Scotland, in 2007. Methods: Scottish maternity records were linked to dispensed prescribing data for all women who gave birth in Tayside in 2007. Drugs prescribed were coded according to the US FDA classification for risks of drugs in pregnancy. Patterns of prescribing were investigated during the 3 trimesters of pregnancy and the 3 months prior to conception. Results: Prescribing in pregnancy was common, with 21 093 prescriptions dispensed to 3356 (85.2%) of the 3937 women. The most frequently prescribed drugs were antacids, antibacterials, oral iron, folic acid preparations and analgesics. Category A drugs (positive evidence of safety in pregnancy) and Category B drugs (some evidence of safety in pregnancy) accounted for 19.6% and 26.9% of all prescriptions dispensed, respectively. Prescribing of Category X drugs (evidence of risk to the fetus; use contraindicated in women who are or may become pregnant) during pregnancy was rare, with 112 prescriptions dispensed to 68 women (1.7%). Most of these were oral contraceptives or sex hormones. Prescribing of Category X drugs fell markedly during the first trimester and remained very low thereafter. Category D drugs (evidence of risk to the fetus but benefits of therapy may outweigh the potential risk) [432] were dispensed to 166 women (4.2%) during pregnancy. The most commonly prescribed Category D drugs were anxiolytics, nicotine replacement therapy and antiepileptic drugs. The frequency of prescribing of Category D drugs reduced in the third trimester. Prescribing of Category C drugs (insufficient evidence to know whether they are harmful) was common. Thirty percent of women received a total of 3641 Category C prescriptions, which accounted for 17.3% of all prescriptions issued during pregnancy. Prescribing of Category C drugs showed only a very modest decline during pregnancy. No FDA code was available for 4035 prescriptions issued (87 different items), the majority of which were for antacids and preparations for indigestion. More than 40% of women received such medications. Conclusions: Prescribing of drugs during pregnancy was very common, but the levels of prescribing of drugs that are known to be harmful were low. Much of the prescribing was for drugs related to the pregnancy. While this study provides some evidence that primary-care prescribers in Tayside are prescribing potentially harmful drugs appropriately and with caution during pregnancy, safety data during pregnancy are unavailable for many drugs that are commonly prescribed