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Introduction Previous studies have suggested that more intensive initial therapy for hypertension results in better long-term blood pressure (BP) control. We test this hypothesis comparing initial monotherapy with dual therapy in the management of essential hypertension. Methods and analysis The study is a prospective, multicentre, double-blind, active-controlled trial in patients with essential hypertension. Around 50% of patients studied will be newly diagnosed and the others will be known hypertensives who previously received only monotherapy. The trial is divided into three phases as follows: Phase 1 (Week 0–Week 16): Randomised, parallel-group, masked assignation to either combination or monotherapy. Phase 2 (Week 17–Week 32): Open-label combination therapy. Phase 3 (Week 33–Week 52): Open-label combination therapy plus open-label add-on (if BP is above 140/90 mm Hg). Hierarchical primary end points are: a comparison of home BP (home systolic blood pressure (HSBP)) averaged over the duration of phase 1 and 2 in the combination versus monotherapy arms. If combination is superior in this analysis, then the averaged mean HSBP between initial monotherapy and initial combination therapy at the end of phase 2 will be compared. Secondary end points include: BP control at 1 year; the role of age, baseline renin, sodium status, plasma volume, haemodynamic compensation and peripheral resistance on BP control; validation of the National Institute for Clinical Excellence/British Hypertension Society joint guideline algorithm; safety and tolerability of combination therapy; and the impact of combination versus monotherapy on left ventricular mass and aortic pulse wave velocity. A sample size of 536 (268 in each group) will have 90% power to detect a difference in means of 4 mm Hg. Ethics and dissemination PATHWAY 1 was approved by UK ethics (REC Reference 09/H0308/132). Trial results will be published and all participating subjects will be informed of the results. Trial registration number UKCRN 4499 and EudraCT number 2008-007749-29 registered 27/08/2009.

Background Our knowledge of the impact of Multiple Sclerosis throughout the UK as a whole is often based on extrapolation from small regional studies. There have been few nationwide studies. Methods We sought to rectify this using the General Practice Research Database (GPRD) to estimate the incidence and prevalence of MS by age, and describe secular trends and geographic variations within the UK over the 20 year period between 1990 and 2010. Results The numbers of patients with up–to–standard follow up time on the GPRD increased from 1.1 million in 1990 to at least 4.0 million between 2006 and 2010. The GPRD population included about 8% of the UK population in 2010, and their age and sex distribution were similar to those of the whole population. During the study period the prevalence of MS increased by about 2.4% per year (95% CI 2.3%, 2.6%) reaching 2,858 per million (pm) in women (95% CI 2,787, 2,931) and 1,131 pm in men (95% CI 1,086, 1,177) by 2010. There was a consistent downward trend in incidence of MS reaching 97.2 pm/yr (95% CI 80.3, 117.5) in women and 48.0 pm/yr (95% CI 39.3, 58.7) in men by 2010. Peak incidence occurred between ages 40–50 years and maximum prevalence between ages 55–60 years. Women accounted for 72% of prevalent and 71% of incident cases. Scotland had the highest proportion of cases of MS with an incidence almost double that of Wales. We looked at the variation in incidence and prevalence rates for MS between UK regions. We found a statistically significant trend in both incidence and prevalence of MS with latitude, but in both cases the significance of the trend was lost when Scotland was excluded from the analysis. There was significant variation in both the incidence and prevalence of MS between different UK regions (p Discussion Our study provides a comprehensive picture of the prevalence and incidence of MS throughout the UK. We estimate that 126,669 people were living with MS in the UK in 2010 (2,034 pm population), and that 6,003 new cases were diagnosed that year (96.4 pm/yr). There is an increasing population living longer with MS, which has important implications for resource allocation for MS in the UK. Funding This study was funded by a grant from the Multiple Sclerosis National Therapy Centres.

Objective To investigate whether exposure to spironolactone treatment affects the risk of incident breast cancer in women over 55 years of age. Design Retrospective, matched cohort study. Setting General Practice Research Database, a primary care anonymised database representative of the general population in the United Kingdom. Participants 1 290 625 female patients, older than 55 years and with no history of breast cancer, from 557 general practices with a total follow-up time of 8.4 million patient years. We excluded patients with poor quality data and those with no contacts with their general practitioner after their current registration date. Intervention Exposed cohort included women who received at least two prescriptions of spironolactone after age 55 years, who were followed up from the first prescription (index date). We randomly selected two unexposed female controls for every exposed patient, matched by practice, year of birth, and socioeconomic scores (if information was available), and followed up from the same date. Main outcome measure New cases of breast cancer, using Read codes to confirm diagnoses. Results Index dates for study patients ranged from 1987 to 2010, and 29 491 new cases of breast cancer were recorded in the study population (incidence rate 0.35% per year). The exposed cohort of 28 032 patients and control cohort of 55 961 patients had unadjusted incidence rates of 0.39% and 0.38% per year, respectively, over a mean follow-up time of 4.1 years. Time-to-event analysis, adjusting for potential risk factors, provided no evidence of an increased incidence of breast cancer in patients exposed to spironolactone (hazard ratio 0.99, 95% confidence interval 0.87 to 1.12). Conclusions These data suggest that the long term management of cardiovascular conditions with spironolactone does not increase the risk of breast cancer in women older than 55 years with no history of the disease.

The combination should be used with caution because of the risk of hyperkalaemia Although much effort goes into understanding the risks and benefits of recently licensed drugs, less is known about many of the older drugs that are prescribed widely. For example, the phrase “safe as aspirin” is often used to extol the safety virtues of a drug, even though aspirin is one of the main culprits when it comes to hospital admissions related to an adverse drug event.1 Spironolactone and trimethoprim-sulfamethoxazole (co-trimoxazole) are two “older” drugs about which we should know more. In the linked case-control study (doi:10.1136/bmj.d5228), Antoniou and colleagues assess the risk of admission to hospital for hyperkalaemia in elderly patients treated with co-trimoxazole in combination with spironolactone.2 Spironolactone works well in congestive heart failure,3 resistant hypertension,4 hyperaldosteronism,5 and hypertension in general.6 Despite hypertension being an unlicensed indication in the United Kingdom, the new guidelines from the National Institute for Health and Clinical Excellence (NICE) on hypertension name spironolactone as an option for fourth line treatment.7 Because of these benefits, the use of …

Steven Bradshaw and colleagues explain the management of that all too common of problems--headaches