Summary Background Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium ...retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure. Methods In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18–79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25–50 mg), bisoprolol (5–10 mg), doxazosin modified release (4–8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081. Findings Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (–8·70 mm Hg 95% CI −9·72 to −7·69; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; −4·26 –5·13 to −3·38; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (–4·03 –5·04 to −3·02; p<0·0001) and versus bisoprolol (–4·48 –5·50 to −3·46; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion. Interpretation Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition. Funding The British Heart Foundation and National Institute for Health Research.
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.
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.
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).
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.
British Heart Foundation and UK National Institute for Health Research.
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.
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.
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).
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Previous studies have suggested that some pet dogs respond to their owners' hypoglycaemic state. Here, we show that trained glycaemia alert dogs placed with clients living with diabetes afford ...significant improvements to owner well-being. We investigated whether trained dogs reliably respond to their owners' hypoglycaemic state, and whether owners experience facilitated tightened glycaemic control, and wider psychosocial benefits. Since obtaining their dog, all seventeen clients studied reported positive effects including reduced paramedic call outs, decreased unconscious episodes and improved independence. Owner-recorded data showed that dogs alerted their owners, with significant, though variable, accuracy at times of low and high blood sugar. Eight out of the ten dogs (for which owners provided adequate records) responded consistently more often when their owner's blood sugars were reported to be outside, than within, target range. Comparison of nine clients' routine records showed significant overall change after obtaining their dogs, with seven clients recording a significantly higher proportion of routine tests within target range after obtaining a dog. HbA1C showed a small, non significant reduction after dog allocation. Based on owner-reported data we have shown, for the first time, that trained detection dogs perform above chance level. This study points to the potential value of alert dogs, for increasing glycaemic control, client independence and consequent quality of life and even reducing the costs of long-term health care.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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, β 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.
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.
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.
British Heart Foundation and National Institute for Health Research.
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.
ObjectivesTo describe the incidence of adverse events (AEs), reactogenicity symptoms, menstrual changes and overall self-rated improvement in health and well-being after COVID-19 ...vaccination.DesignVAC4COVID is an ongoing prospective, active observational, post-authorisation cohort safety study (PASS) of UK-approved vaccines for COVID-19 disease.SettingThe study is conducted through a secure website (www.vac4covid.com) by MEMO Research, University of Dundee, UK.Participants16 265 adult (18 years or older) UK residents with a valid email address and internet access.InterventionsAny UK-authorised COVID-19 vaccination.Main outcome measuresThe outcomes reported in this interim analysis include AEs, reactogenicity-type AEs (headache, fatigue, muscle or joint pain, fever, nausea, dizziness or local vaccine reaction), menstrual changes and reported improvement in overall health and well-being.Results11 475 consented participants (mean age 54.8 years) provided follow-up data between 2 February and 5 October 2021 (mean follow-up duration 184 days), by which date 89.2% of participants had received two vaccine doses. 89.8% of 5222 participants who completed a follow-up questionnaire in the 7 days after any COVID-19 vaccination reported no AEs. The risk of experiencing any event (not necessarily vaccine-related) requiring hospitalisation was less than 0.2%. 43.7% of post-vaccination follow-up records reported improvement in health and well-being. Reactogenicity-type reactions were more common in the week after the first dose of ChAdOx1 than BNT162b2 (7.8% vs 1.6%), but this relationship was reversed after the second dose (1.3% vs 3.1%). 0.3% of women reported menstrual symptoms after vaccination; no differences between vaccine type or dose order were detected.ConclusionsThe study provides reassuring data on low rates of AEs after COVID-19 vaccination. Differences in reactogenicity-type AE profiles between ChAdOx1 and BNT162b2 and between first and second doses of these vaccines were observed.Trial registration numberISRCTN95881792; Pre-results.
•Diabetes Alert Dogs show differences in behaviour when their owner’s glucose levels fluctuate.•Dogs elicit trained and non-trained behaviours when their owner transitions to hypo- or ...hyperglycaemia.•Variation in the occurrence of attention-seeking behaviours was shown by all dogs.•Despite undergoing the same training, dogs showed individual profiles of behaviour change.
Owner-independent assessments of Diabetes Alert Dog (DAD) behaviour post-placement are currently lacking. Here we describe the first study to simultaneously collect objective DAD behavioural data from CCTV footage and concurrent owner glucose levels via a Flash Glucose Monitoring System (FGMS). Using a pre-defined behavioural ethogram, both trained and non-trained canine behaviours were recorded. Given that dogs are trained to display attention-seeking behaviours when their owners experience fluctuations outside of normal blood glucose levels, we would expect differences in DAD behaviour during periods when owner glucose levels transition from euglycaemia to hyperglycaemic (high) or hypoglycaemic (low) levels, as compared to periods when owners stay within target-range.
A FreeStyle Libre FGMS was given to nine owners of accredited DADs from a single training establishment. Behavioural data were collected using CCTV in the participants' home, or place of work, for between five and 14 days (mean = 12.2 days). For each person, between 19 and 29 (mean = 22.5) one-hour periods were selected that captured approximately equal instances of owner glucose levels transitioning from in-range to hypoglycaemia, in-range to hyperglycaemia, or remaining within target-range. Two researchers coded footage without knowledge of the owner's glucose levels. Variables recorded included the DAD's Activity, Attentional State, Proximity to Owner, Attention-seeking, and potential Stress-related behaviours.
There were significant differences between individual dogs' behaviour during in-range periods. When samples captured a transition to out-of-range glucose levels (hypo- or hyperglycaemia), the distribution of several behaviours among dogs in the cohort differed significantly from their distributions during in-range samples (p < 0.01 for Conover Tests in Playing with Owner, Jump Up, Sniff Owner, Bark, Paw Owner, and Lick Owner), but consistent increases or decreases in the rate of any behaviours were not detected across the cohort. In individual dogs, we found distinctive behaviour changes during periods when their owner's glucose transitioned to out-of-range, as compared to when they remained in-range. Each DAD showed significant changes in the variance of at least one trained attention-seeking behaviour, with several dogs also showing changes in non-trained behaviours such as Change of State, Playing with Owner and potential stress-related behaviours (Yawning and Lip-Licking). This is the first study to objectively show that DADs differ in their behaviour during periods of owner glucose fluctuation and further highlights the individuality of responses. Understanding this variation, and factors affecting it, is fundamental to optimising DAD performance.
Healthcare systems must use treatments that are effective and safe. Regulators licensed many currently used older medications before introducing the stringent evidential requirements imposed on ...modern treatments. Also, there has been little encouragement to carry out within-class, head-to-head comparisons of licensed medicines. For commonly prescribed drugs, even small differences in effectiveness or safety could have significant public health implications. However, conventional clinical trials that randomise individual subjects are costly and unwieldy. Such trials are also often criticised as having low external validity. We describe an approach to rapidly generate externally valid evidence of comparative safety and effectiveness using the example of two widely used diuretics for the management of hypertension.
The EVIDENCE (Evaluating Diuretics in Normal Care) study has a prospective, cluster-randomised, open-label, blinded end-point design. By randomising prescribing policy in primary care practices, the study compares the safety and effectiveness of commonly used diuretics in treating hypertension. Participating practices are randomised 1:1 to a policy of prescribing either indapamide or bendroflumethiazide when clinically indicated. Suitable patients who are not already taking the policy diuretic are switched accordingly. All patients taking the study medications are written to explaining the rationale for changing the prescribing policy and notifying them they can opt-out of any switch. The prescribing policies' effectiveness and safety will be compared using rates of major adverse cardiovascular events (hospitalisation with myocardial infarction, heart failure or stroke or cardiovascular death), routinely collected in national healthcare administrative datasets. The study will seek to recruit 250 practices to provide a study population of approximately 50,000 individuals with a mean follow-up time of two years. A primary intention-to-treat time-to-event analysis will be used to estimate the relative effect of the two policies.
EVIDENCE has been approved by the East of Scotland Research Ethics Service (17/ES/0016, current approved protocol version 5, 26 August 2021). The results will be disseminated widely in peer reviewed journals, guideline committees, National Health Service (NHS) organisations and patient groups.
ISRCTN 46635087 . Registered on 11 August 2017 (pre-recruitment).
Lamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate ...the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment.
SPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12-24 and 0-24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored.
Treatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12-24 months p=0.043, Nfh 0-24 months p=0.023). Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand), PASAT, z-score, MSIS-29 (psychological) and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin.
The relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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