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 < 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. Funding: The TIME study was funded by the British Heart Foundation (CS/14/1/30659) with support from the British and Irish Hypertension Society.

Impact of EMA regulatory label changes on systemic diclofenac initiation, discontinuation, and switching to other pain medicines in Scotland, England, Denmark, and The Netherlands.

PURPOSE: In June 2013 a European Medicines Agency referral procedure concluded that diclofenac was associated with an elevated risk of acute cardiovascular events and contraindications, warnings, and changes to the product information were implemented across the European Union. This study measured the impact of the regulatory action on the prescribing of systemic diclofenac in Denmark, The Netherlands, England, and Scotland. METHODS: Quarterly time series analyses measuring diclofenac prescription initiation, discontinuation and switching to other systemic nonsteroidal anti-inflammatory (NSAIDs), topical NSAIDs, paracetamol, opioids, and other chronic pain medication in those who discontinued diclofenac. Absolute effects were estimated using interrupted time series regression. RESULTS: Overall, diclofenac prescription initiations fell during the observation periods of all countries. Compared with Denmark where there appeared to be a more limited effect, the regulatory action was associated with significant immediate reductions in diclofenac initiation in The Netherlands (-0.42%, 95% CI, -0.66% to -0.18%), England (-0.09%, 95% CI, -0.11% to -0.08%), and Scotland (-0.67%, 95% CI, -0.79% to -0.55%); and falling trends in diclofenac initiation in the Netherlands (-0.03%, 95% CI, -0.06% to -0.01% per quarter) and Scotland (-0.04%, 95% CI, -0.05% to -0.02% per quarter). There was no significant impact on diclofenac discontinuation in any country. The regulatory action was associated with modest differences in switching to other pain medicines following diclofenac discontinuation. CONCLUSIONS: The regulatory action was associated with significant reductions in overall diclofenac initiation which varied by country and type of exposure. There was no impact on discontinuation and variable impact on switching.

How effective are trained dogs at alerting their owners to changes in blood glycaemic levels?: Variations in performance of glycaemia alert dogs.

AIMS: Domestic dogs are trained to a wide variety of roles including an increasing number of medical assistance tasks. Glycaemia alert dogs are reported to greatly improve the quality of life of owners living with Type 1 diabetes. Research into their value is currently sparse, on small numbers of dogs and provides conflicting results. In this study we assess the reliability of a large number of trained glycaemic alert dogs at responding to hypo- and hyper-glycaemic (referred to as out-of-range, OOR) episodes, and explore factors associated with variations in their performance. METHODS: Routine owner records were used to assess the sensitivity and specificity of each of 27 dogs, trained by a single UK charity during almost 4000 out-of-range episodes. Sensitivity and positive predictive values are compared to demographic factors and instructors' ratings of the dog, owner and partnership. RESULTS: Dogs varied in their performance, with median sensitivity to out-of-range episodes at 70% (25th percentile = 50, 75th percentile = 95). To hypoglycaemic episodes the median sensitivity was 83% (66-94%) while to hyperglyaemic episodes it was 67% (17-91%). The median positive predictive value (PPV) was 81% (68-94%), i.e. on average 81% of alerts occurred when glucose levels were out of target range. For four dogs, PPV was 100%. Individual characteristics of the dog, the partnership and the household were significantly associated with performance (e.g., whether the dog was previously a pet, when it was trained, whether its partner was an adult or child). CONCLUSIONS: The large sample shows that the individual performance of dogs is variable, but overall their sensitivity and specificity to OOR episodes are better than previous studies suggest. Results show that optimal performance of glycaemic alert dogs depends not only on good initial and ongoing training, but also careful selection of dogs for the conditions in which they will be working.

Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies.

BACKGROUND: In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension. METHODS: PATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25-50 mg, bisoprolol 5-10 mg, and doxazosin 4-8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10-20 mg once daily on clinic systolic blood pressure during an optional 6-12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008-007149-30, and ClinicalTrials.gov, number NCT02369081. FINDINGS: Of the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r2=0·13, p<0·0001) and plasma renin (r2=0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17-33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from baseline (95% CI 4·0 to 8·8; p<0·0001) with spironolactone, but not other treatments. Amiloride (10 mg once daily) reduced clinic systolic blood pressure by 20·4 mm Hg (95% CI 18·3-22·5), compared with a reduction of 18·3 mm Hg (16·2-20·5) with spironolactone (25 mg once daily). No serious adverse events were recorded, and adverse symptoms were not systematically recorded after the end of the double-blind treatment. Mean plasma potassium concentrations increased from 4·02 mmol/L (95% CI 3·95-4·08) on placebo to 4·50 (4·44-4·57) on amiloride (p<0·0001). INTERPRETATION: Our results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension. FUNDING: British Heart Foundation and UK National Institute for Health Research.

Acid-suppression medications and bacterial gastroenteritis: a population-based cohort study.

AIMS: To investigate whether acid-suppression medicines (ASMs) increase the risk of bacterial gastroenteritis. METHODS: A population-based, propensity-score matched cohort study using a record-linkage database in Tayside, UK. The study consisted of 188 323 exposed to ASMs (proton-pump inhibitors and histamine-2 receptor antagonists) and 376 646 controls (a propensity-score matched cohort from the rest of population who were not exposed to ASMs) between 1999 and 2013. The main outcome measure was a positive stool test for Clostridium difficile, Campylobacter, Salmonella, Shigella or Escherichia coli O157. The association between ASMs and risk of bacterial gastroenteritis was assessed by a Cox regression model. RESULTS: There were 22 705 positive test results (15 273 C. difficile [toxin positive], 6590 Campylobacter, 852 Salmonella, 129 Shigella and 193 E. coli O157, not mutually exclusive) with a total of 5 729 743 person-years follow up time in Tayside, 1999-2013. The adjusted hazard ratios for culture positive diarrhoea for the proton-pump inhibitors and histamine-2 receptor antagonists exposed vs. unexposed cohort were 2.72 (95% confidence interval [CI] 2.33, 3.17) during follow-up time for samples submitted from the community and 1.28 (95% CI 1.08, 1.52) for samples submitted from hospitals. Compared with the unexposed cohort, patients in the exposed group had increased risks of C. difficile and Campylobacter [adjusted hazard ratios of 1.70 (95% CI 1.28, 2.25), 3.71 (95% CI 3.04, 4.53) for community samples, and 1.42 (95% CI 1.17, 1.71), 4.53 (95% CI 1.75, 11.8) for hospital samples, respectively]. CONCLUSIONS: The results suggest that community prescribed ASMs were associated with increased rates of C. difficile and Campylobacter positive gastroenteritis in both the community and hospital settings.

Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): a parallel-group, double-blind randomised phase 4 trial.

BACKGROUND: Potassium depletion by thiazide diuretics is associated with a rise in blood glucose. We assessed whether addition or substitution of a potassium-sparing diuretic, amiloride, to treatment with a thiazide can prevent glucose intolerance and improve blood pressure control. METHODS: We did a parallel-group, randomised, double-blind trial in 11 secondary and two primary care sites in the UK. Eligible patients were aged 18-80 years; had clinic systolic blood pressure of 140 mm Hg or higher and home systolic blood pressure of 130 mmHg or higher on permitted background drugs of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, ß blockers, calcium-channel blockers, or direct renin inhibitors (previously untreated patients were also eligible in specific circumstances); and had at least one component of the metabolic syndrome in addition to hypertension. Patients with known diabetes were excluded. Patients were randomly assigned (1:1:1) to 24 weeks of daily oral treatment with starting doses of 10 mg amiloride, 25 mg hydrochlorothiazide, or 5 mg amiloride plus 12·5 mg hydrochlorothiazide; all doses were doubled after 12 weeks. Random assignment was done via a central computer system. Both participants and investigators were masked to assignment. Our hierarchical primary endpoints, assessed on a modified intention-to-treat basis at 12 and 24 weeks, were the differences from baseline in blood glucose measured 2 h after a 75 g oral glucose tolerance test (OGTT), compared first between the hydrochlorothiazide and amiloride groups, and then between the hydrochlorothiazide and combination groups. A key secondary endpoint was change in home systolic blood pressure at 12 and 24 weeks. This trial is registered with ClinicalTrials.gov, number NCT00797862, and the MHRA, Eudract number 2009-010068-41, and is now complete. FINDINGS: Between Nov 18, 2009, and Dec 15, 2014, 145 patients were randomly assigned to amiloride, 146 to hydrochlorothiazide, and 150 to the combination group. 132 participants in the amiloride group, 134 in the hydrochlorothiazide group, and 133 in the combination group were included in the modified intention-to-treat analysis. 2 h glucose concentrations after OGTT, averaged at 12 and 24 weeks, were significantly lower in the amiloride group than in the hydrochlorothiazide group (mean difference -0·55 mmol/L [95% CI -0·96 to -0·14]; p=0·0093) and in the combination group than in the hydrochlorothiazide group (-0·42 mmol/L [-0·84 to -0·004]; p=0·048). The mean reduction in home systolic blood pressure during 24 weeks did not differ significantly between the amiloride and hydrochlorothiazide groups, but the fall in blood pressure in the combination group was significantly greater than that in the hydrochlorothiazide group (p=0·0068). Hyperkalaemia was reported in seven (4·8%) patients in the amiloride group and three (2·3%) patients in the combination group; the highest recorded potassium concentration was 5·8 mmol/L in a patient in the amiloride group. 13 serious adverse events occurred but the frequency did not differ significantly between groups. INTERPRETATION: The combination of amiloride with hydrochlorothiazide, at doses equipotent on blood pressure, prevents glucose intolerance and improves control of blood pressure compared with montherapy with either drug. These findings, together with previous data about morbidity and mortality for the combination, support first-line use of amiloride plus hydrochlorothiazide in hypertensive patients who need treatment with a diuretic. FUNDING: British Heart Foundation and National Institute for Health Research.

An observational descriptive study of the epidemiology and treatment of neuropathic pain in a UK general population.

BACKGROUND: This study updated our knowledge of UK primary care neuropathic pain incidence rates and prescribing practices. METHODS: Patients with a first diagnosis of post-herpetic neuralgia (PHN), painful diabetic neuropathy (PDN) or phantom limb pain (PLP) were identified from the General Practice Research Database (2006 - 2010) and incidence rates were calculated. Prescription records were searched for pain treatments from diagnosis of these conditions and the duration and daily dose estimated for first-line and subsequent treatment regimens. Recording of neuropathic back and post-operative pain was investigated. RESULTS: The study included 5,920 patients with PHN, 5,340 with PDN, and 185 with PLP. The incidence per 10,000 person-years was 3.4 (95% CI 3.4, 3.5) for PHN; and 0.11 (95% CI 0.09, 0.12) for PLP. Validation of the PDN case definition suggested that was not sensitive. Incident PHN increased over the study period. The most common first-line treatments were amitriptyline or gabapentin in the PDN and PLP cohorts, and amitriptyline or co-codamol (codeine-paracetamol) in PHN. Paracetamol, co-dydramol (paracetamol-dihydrocodeine) and capsaicin were also often prescribed in one or more condition. Most first-line treatments comprised only one therapeutic class. Use of antiepileptics licensed for neuropathic pain treatment had increased since 2002-2005. Amitriptyline was the only antidepressant prescribed commonly as a first-line treatment. CONCLUSION: The UK incidence of diagnosed PHN has increased with the incidence of back-pain and post-operative pain unclear. While use of licensed antiepileptics increased, prescribing of therapy with little evidence of efficacy in neuropathic pain is still common and consequently treatment was often not in-line with current guidance.

Drug treatment discontinuation and achievement of target blood pressure and cholesterol in United Kingdom primary care.

AIM: This cohort study evaluated medication discontinuation and target achievement in a United Kingdom primary care setting. METHODS: The study population comprised patients within the General Practice Research Database who began treatment for hypertension, dyslipidaemia or both between 1997 and 2001. Discontinuation (absence of prescription refill > or = 6 months) and reaching treatment targets (blood pressure < 140/90 mmHg, or < 130/80 mmHg in patients with diabetes; total cholesterol < 193 mg/dL [5 mmol/L] or low-density lipoprotein cholesterol < 116 mg/dL [3 mmol/L]) were determined for patients treated for hypertension alone (cohort HT), dyslipidaemia alone (cohort DYS) and both conditions (cohort HT+DYS). RESULTS: At 2 years, 41.3% (95% CI: 40.8, 41.9%) of patients had stopped treatment in cohort HT, 29.2% (27.6, 30.9%) in cohort DYS and 25.0% (24.3, 25.8%) stopped either treatment in cohort HT+DYS. The cumulative proportion reaching treatment targets at this time was 28.2% (27.8, 28.7%) in cohort HT and 49.9% (47.8, 51.9%) in cohort DYS; in cohort HT+DYS, 43.4% (42.6, 44.2%) achieved blood pressure target, 53.7% (52.8, 54.6%) cholesterol target and 24.8% (24.0, 25.5%) reached target for both. Diabetic patients generally stayed on treatment longer and were less likely to attain their blood pressure targets, and more likely to reach cholesterol targets, compared with all patients. CONCLUSION: Patients prescribed both antihypertensive and lipid-lowering therapy remained on treatment longer; more patients achieved treatment target than those treated for single risk factors. Nevertheless, there is a large unmet need for initiating and maintaining antihypertensive and lipid-lowering therapy in patients with hypertension and dyslipidaemia.