Dietary nitrate prevents progression of carotid subclinical atherosclerosis through blood pressure-independent mechanisms in patients with or at risk of type 2 diabetes mellitus.

AIMS: To test if 6 months' intervention with dietary nitrate and spironolactone could affect carotid subclinical atherosclerosis and stiffness, respectively, vs. placebo/doxazosin, to control for blood pressure (BP). METHODS: A subgroup of participants in our double-blind, randomized-controlled, factorial VaSera trial had carotid imaging. Patients with hypertension and with/at risk of type 2 diabetes were randomized to active nitrate-containing beetroot juice or placebo nitrate-depleted juice, and spironolactone or doxazosin. Vascular ultrasound for carotid diameter (CD, mm) and intima-media thickness (CIMT, mm) was performed at baseline, 3- and 6-months. Carotid local stiffness (CS, m/s) was estimated from aortic pulse pressure (Arteriograph) and carotid lumen area. Data were analysed by modified intention to treat and using mixed-model effect, adjusted for confounders. RESULTS: In total, 93 subjects had a baseline evaluation and 86% had follow-up data. No statistical interactions occurred between the juice and drug arms and BP was similar between the juices and between the drugs. Nitrate-containing vs. placebo juice significantly lowered CIMT (-0.06 [95% confidence interval -0.12, -0.01], P = .034), an overall difference of ~8% relative to baseline; but had no effect on CD or CS. Doxazosin appeared to reduce CS from baseline (-0.34 [-0.62, -0.06]) however, no difference was detected vs. spironolactone (-0.15 [-0.46, 0.16]). No differences were detected between spironolactone or doxazosin on CIMT and CD. CONCLUSIONS: Our results show that 6 months' intervention with dietary nitrate influences vascular remodelling, but not carotid stiffness or diameter. Neither spironolactone nor doxazosin had a BP-independent effect on carotid structure and function.

Impact of EMA regulatory label changes on hydroxyzine initiation, discontinuation and switching to other medicines in Denmark, Scotland, England and the Netherlands: An interrupted time series regression analysis.

BACKGROUND: Hydroxyzine is indicated for the management of anxiety, skin and sleep disorders. In 2015, the European Medicines Agency (EMA) concluded that hydroxyzine was pro-arrhythmogenic and changes to the product information were implemented in Europe. This study aimed to evaluate their impact in Denmark, Scotland, England and the Netherlands. METHOD: Quarterly time series analyses measuring hydroxyzine initiation, discontinuation, and switching to other antihistamines, benzodiazepines and antidepressants in Denmark, England, Scotland and the Netherlands from 2009 to 2018. Data were analysed using interrupted time series regression. RESULTS: Hydroxyzine initiation in quarter one 2010 in Denmark, Scotland, England and the Netherlands per 100 000 was: 23.5, 91.5, 35.9 and 34.4 respectively. Regulatory action was associated with a significant: immediate fall in hydroxyzine initiation per 100 000 in England (-12.05, 95%CI -18.47 to -5.63) and Scotland (-19.01, 95%CI -26.99 to -11.02); change to a negative trend in hydroxyzine initiation per 100 000/quarter in England (-1.72, 95%CI -2.69 to -0.75) and Scotland (-2.38, 95%CI -3.32 to -1.44). Regulatory action was associated with a significant: immediate rise in hydroxyzine discontinuation per 100 000 in England (3850, 95%CI 440-7240). No consistent changes were observed in the Netherlands or Denmark. Regulatory action was associated with no switching to other antihistamines, benzodiazepines or antidepressants following hydroxyzine discontinuation in any country. CONCLUSION: The 2015 EMA regulatory action was associated with heterogeneous impact with reductions in hydroxyzine initiation varying by country. There was limited impact on discontinuation with no strong evidence suggesting unintended consequences of major switching to other antihistamines, benzodiazepines or antidepressants.

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.

A randomised, factorial trial to reduce arterial stiffness independently of blood pressure: Proof of concept? The VaSera trial testing dietary nitrate and spironolactone.

AIMS: To test if spironolactone or dietary nitrate from beetroot juice could reduce arterial stiffness as aortic pulse wave velocity (PWVart), a potential treatment target, independently of blood pressure. METHODS: Daily spironolactone (≤50 mg) vs doxazosin (control ≤16 mg) and 70 mL beetroot juice (Beet-It ≤11 mmol nitrate) vs nitrate-depleted juice (placebo; 0 mmol nitrate) were tested in people at risk or with type-2 diabetes using a double-blind, 6-month factorial trial. Vascular indices (baseline, 12, 24 weeks) were cardiac-ankle vascular index (CAVI), a nominally pressure-independent stiffness measure (primary outcome), PWVart secondary, central systolic pressure and augmentation. Analysis was intention-to-treat, adjusted for systolic pressure differences between trial arms. RESULTS: Spironolactone did not reduce stiffness, with evidence for reduced CAVI on doxazosin rather than spironolactone (mean difference [95% confidence interval]; 0.25 [-0.3, 0.5] units, P = .080), firmer for PWVart (0.37 [0.01, 0.7] m/s, P = .045). There was no difference in systolic pressure reduction between spironolactone and doxazosin (0.7 [-4.8, 3.3] mmHg, P = .7). Circulating nitrate and nitrite increased on active vs placebo juice, with central systolic pressure lowered -2.6 [-4.5, - 0.8] mmHg, P = .007 more on the active juice, but did not reduce CAVI, PWVart or peripheral pressure. Change in nitrate and nitrite concentrations were 1.5-fold [1.1-2.2] and 2.2-fold [1.3, 3.6] higher on spironolactone than on doxazosin respectively; both P < .05. CONCLUSION: Contrary to our hypothesis, in at-risk/type 2 diabetes patients, spironolactone did not reduce arterial stiffness, rather PWVart was lower on doxazosin. Dietary nitrate elevated plasma nitrite, selectively lowering central systolic pressure, observed previously for nitrite.

Cardiac effects of 6 months' dietary nitrate and spironolactone in patients with hypertension and with/at risk of type 2 diabetes, in the factorial design, double-blind, randomized controlled VaSera trial.

AIMS: The aims of the present study were to explore whether a long-term intervention with dietary nitrate [(NO3- ), a potential tolerance-free source of beneficial vasoactive nitric oxide] and spironolactone (to oppose aldosterone's potential deleterious cardiovascular effects) improve cardiac structure/function, independently of blood pressure (BP), in patients with/at risk of type 2 diabetes (a population at risk of heart failure). METHODS: A subsample of participants in our double-blind, randomized, factorial-design intervention (VaSera) trial of active beetroot juice as a nitrate source (≤11.2 mmol) or placebo (nitrate depleted) beetroot juice, and either ≤50 mg spironolactone or ≤16 mg doxazosin (control), had transthoracic cardiac ultrasounds at baseline (n = 105), and at 3 months and 6 months (n = 87) after the start of the intervention. Analysis was by modified intent-to-treat. RESULTS: Nitrate-containing juice (n = 40) decreased left ventricular (LV) end-diastolic volume {-6.3 [95% confidence interval (CI) -11.1, -1.6] ml} and end-systolic volume [-3.2 (95% CI -5.9, -0.5) ml], and increased end-diastolic mass/volume ratio [+0.04 (95% CI 0.00, 0.07)], relative to placebo juice (n = 47). Spironolactone (n = 44) reduced relative wall thickness compared with doxazosin (n = 43) [-0.01 (95% CI -0.02, -0.00)]. Although spironolactone reduced LV mass index relative to baseline [-1.48 (95% CI -2.08, -0.88) g m-2.7 ], there was no difference vs. doxazosin [-0.85 (95% CI -1.76, 0.05) g m-2.7 ]. Spironolactone also decreased the E/A ratio [-0.12 (95% CI -0.19, -0.04)] and increased S' (a tissue-Doppler systolic function index) by 0.52 (95% CI 0.05, 1.0) cm s-1 . BP did not differ between the juices, or between the drugs. CONCLUSIONS: Six months' dietary nitrate decreased LV volumes ~5%, representing new, sustained, BP-independent benefits on cardiac structure, extending mechanisms characterized in preclinical models of heart failure. Spironolactone's effects on cardiac remodelling and systolic-diastolic function, although confirmatory, were independent of BP.

Spironolactone use and risk of incident cancers: a retrospective, matched cohort study.

AIMS: Spironolactone is widely used to treat heart failure, hypertension and liver disease with increased usage in recent years. Spironolactone has endocrine effects that could influence cancer risks and historical reports suggest possible links with increased risk of certain types of cancer. The aim of this study was to assess the effect of spironolactone exposure on cancer incidence. METHODS: A pharmacoepidemiological propensity score-matched cohort study was performed to assess the effect of spironolactone exposure on cancer incidence. Cox proportional hazards models were used to analyse time to first diagnosis of each prespecified cancer and hazard ratios for spironolactone exposure are presented. The setting for the study was UK primary care using the Clinical Practice Research Datalink. The participants were 74 272 patients exposed to spironolactone between 1986 and 2013, matched 1:2 with unexposed controls. The prespecified primary outcomes were the first incidence of ovarian, endometrial, pancreatic, colorectal, prostate, renal cell, pharyngeal and thyroid cancers, and myelomonoblastic/-cytic leukaemias. Secondary outcomes were the remaining 27 types of cancer. RESULTS: There was no evidence of an increased risk of any cancer associated with spironolactone use. Spironolactone use was associated with a significantly lower risk of prostate cancer (hazard ratio 0.69; 95% confidence interval 0.60-0.80, P < 0.001). CONCLUSIONS: In this study, spironolactone use was associated with a lower incidence of prostate cancer, the most common cancer in men in the UK. The possible mechanisms and clinical implications merit further investigation.

Increased sexual dysfunction in men with storage and voiding lower urinary tract symptoms.

INTRODUCTION: Sexual dysfunction (SD) and lower urinary tract symptoms (LUTS) are highly prevalent in men and increase with age. Previous studies have shown that LUTS and SD are highly associated in men, but most have not distinguished between voiding and storage LUTS. Aims. Assess impact of voiding and storage LUTS on recorded diagnosis of SD in men in U.K. general practice. METHODS: Identified records of patients with SD and storage (e.g., overactive bladder) and voiding LUTS (e.g., benign prostatic hyperplasia) from a population-based study using The Health Improvement Network database with records from 333 general practices. Study period was 2000-2007; study population was men aged >or= 18 years. MAIN OUTCOME MEASURES: Prevalence rates of SD, and storage and voiding LUTS on January 1 of each year from 2000 to 2007. RESULTS: Overall prevalence of recorded SD rose from 1.7% in 2000 to 4.9% in 2007. The prevalence of storage and voiding LUTS also increased. Median age at diagnosis was 60 years for erectile dysfunction (ED), 62 years for other SD, 62 years for storage LUTS, and 61 years for voiding LUTS. Compared to men with no LUTS, odds ratios (95% CI) for ED were as follows: storage LUTS, 3.0 (2.6-3.4); voiding LUTS, 2.6 (2.4-2.7); and both voiding and storage LUTS, 4.0 (3.4-4.8). Among the 11,327 men with any recorded LUTS and ED at the beginning of 2007, LUTS diagnosis preceded SD in 63.1% of patients by a mean of 4.8 years. CONCLUSIONS: Prevalence of SD was significantly higher in the presence of either storage or voiding LUTS compared to men with no recorded LUTS. The diagnosis of LUTS preceded SD in the majority of cases. Further research into the interrelationships between functional problems of the genitourinary tract may have implications for current treatment approaches and future therapeutic developments.

Prevalence and treatment of isolated and concurrent hypertension and hypercholesterolaemia in the United Kingdom.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The 1998 and 2003 Health Survey for England revealed a high prevalence of hypertension and hypercholesterolaemia in the population of England. Major changes in the reimbursement of primary care for the management of both hypertension and hypercholesterolaemia have occurred in the UK. WHAT THIS STUDY ADDS: Using a GP database we have examined the proportion of subjects diagnosed and treated for hypertension and hypercholesterolaemia over time. To examine the true population rates and primary care data we compared the results of the Health survey for England in both 1998 and 2003 with the recorded data on GP computers. Despite current guidelines, many patients with hypertension and/or hypercholesterolaemia are under-treated and, even amongst those who are treated, many do not achieve their blood pressure and/or lipid targets. Although treatment rates in the UK have improved recently, particularly for lipid-lowering therapies, they remain suboptimal. AIMS To determine the prevalence and treatment of hypertension, dyslipidaemia and both together in the UK between 1998 and 2006. METHODS: We used The Health Improvement Network (THIN) a general practice-based database from 1998 to 2006 and we compared the 1998 and 2003 data to that taken from the Health Survey for England (HSE) in 1998 and 2003. RESULTS: The prevalence (treatment) of hypertension was 25.3% (11.4%) in 1998, 27.8% (15.1%) in 2003 and 26.9% (16.2%) in 2006 in THIN. In HSE it was 37.3% (9.6%) in 1998 and 32.9% (13.8%) in 2003. For dyslipidaemia the figures were 8.6% (1.9%), 18.5% (6.5%) and 24.4% (9.8%) for THIN and 67.8% (2.3%) and 74.9% (7.0%) for HSE. Concurrent hypertension and dyslipidaemia in THIN increased from 5.5% (1.1%) in 1998 to 13.5% (4.5%) in 2003 and 17.4% (7.1%) in 2006. The prevalence of both conditions was 30.6% (0.7%) in HSE in 1998 and 28.7% (3.1%) in 2003. CONCLUSIONS: There has been a progressive improvement in the detection and treatment of hypertension, dyslipidaemia and both conditions together between 1998 and 2006. However, much still needs to be done to improve the diagnosis and treatment of hypertension, hypercholesterolaemia and concurrent hypertension and hypercholesterolaemia in the United Kingdom.

Factors that predict changing the type of phosphodiesterase type 5 inhibitor medication among men in the UK.

OBJECTIVE: To evaluate predictors of changing the type of phosphodiesterase type 5 (PDE5) inhibitor (switching) among men with erectile dysfunction (ED) in the UK, the largest consumer of PDE5 inhibitors in Europe, as switching medication is often associated with higher resource use, and there are three oral PDE5 inhibitor medications currently available. PATIENTS AND METHODS: Patients were identified from The Health Improvement Network database in the UK; men initiating therapy with sildenafil, tadalafil or vardenafil from May 2003 to August 2004 with >/= 6 months of prescription history before and after their initial PDE5 inhibitor prescription were included. Switching was evaluated as the proportion of second PDE5 inhibitor prescriptions that were for a drug differing from the first. Logistic regression was used to adjust for factors that might be associated with switching (dose, age and the presence of hypertension, dyslipidaemia, diabetes or depression). RESULTS: Of the 2703 eligible men who initiated PDE5 inhibitor treatment during the study period, 91 (3.4%) switched to a different PDE5 inhibitor at their second prescription. The choice of initial PDE5 inhibitor therapy was a highly significant predictor of switching; men initiated on sildenafil were less likely to switch than those initiated on tadalafil (P < 0.001) or vardenafil (P < 0.003). Age and the presence of comorbidities were not significantly associated with switching (P > 0.05). CONCLUSION: Initiating ED therapy with sildenafil was associated with the lowest rate of PDE5 inhibitor switching, which might reflect treatment satisfaction and patient preference.