Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial


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.


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, andClinicalTrials.gov number, NCT02369081.


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.


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.


The British Heart Foundation and National Institute for Health Research.

Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial by Bryan Williams et al.

Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study


Alcohol consumption is proposed to be the third most important modifiable risk factor for death and disability. However, alcohol consumption has been associated with both benefits and harms, and previous studies were mostly done in high-income countries. We investigated associations between alcohol consumption and outcomes in a prospective cohort of countries at different economic levels in five continents.


We included information from 12 countries participating in the Prospective Urban Rural Epidemiological (PURE) study, a prospective cohort study of individuals aged 35–70 years. We used Cox proportional hazards regression to study associations with mortality (n=2723), cardiovascular disease (n=2742), myocardial infarction (n=979), stroke (n=817), alcohol-related cancer (n=764), injury (n=824), admission to hospital (n=8786), and for a composite of these outcomes (n=11 963).


We included 114 970 adults, of whom 12 904 (11%) were from high-income countries (HICs), 24 408 (21%) were from upper-middle-income countries (UMICs), 48 845 (43%) were from lower-middle-income countries (LMICs), and 28 813 (25%) were from low-income countries (LICs). Median follow-up was 4·3 years (IQR 3·0–6·0). Current drinking was reported by 36 030 (31%) individuals, and was associated with reduced myocardial infarction (hazard ratio [HR] 0·76 [95% CI 0·63–0·93]), but increased alcohol-related cancers (HR 1·51 [1·22–1·89]) and injury (HR 1·29 [1·04–1·61]). High intake was associated with increased mortality (HR 1·31 [1·04–1·66]). Compared with never drinkers, we identified significantly reduced hazards for the composite outcome for current drinkers in HICs and UMICs (HR 0·84 [0·77–0·92]), but not in LMICs and LICs, for which we identified no reductions in this outcome (HR 1·07 [0·95–1·21]; pinteraction<0·0001).


Current alcohol consumption had differing associations by clinical outcome, and differing associations by income region. However, we identified sufficient commonalities to support global health strategies and national initiatives to reduce harmful alcohol use.


Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, GlaxoSmithKline, Novartis, King Pharma, and national or local organisations in participating countries.

Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study by Andrew Smyth et al.

Prostate Cancer Incidence and PSA Testing Patterns in Relation to USPSTF Screening Recommendations

Importance  Prostate cancer incidence in men 75 years and older substantially decreased following the 2008 US Preventive Services Task Force (USPSTF) recommendation against prostate-specific antigen (PSA)–based screening for this age group. It is unknown whether incidence has changed since the USPSTF recommendation against screening for all men in May 2012.

Objective  To examine recent changes in stage-specific prostate cancer incidence and PSA screening rates following the 2008 and 2012 USPSTF recommendations.

Design and Settings  Ecologic study of age-standardized prostate cancer incidence (newly diagnosed cases/100 000 men aged ≥50 years) by stage from 2005 through 2012 using data from 18 population-based Surveillance, Epidemiology, and End Results (SEER) registries and PSA screening rate in the past year among men 50 years and older without a history of prostate cancer who responded to the 2005 (n = 4580), 2008 (n = 3476), 2010 (n = 4157), and 2013 (n = 6172) National Health Interview Survey (NHIS).

Exposures  The USPSTF recommendations to omit PSA-based screening for average-risk men.

Main Outcomes and Measures  Prostate cancer incidence and incidence ratios (IRs) comparing consecutive years from 2005 through 2012 by age (≥50, 50-74, and ≥75 years) and SEER summary stage categorized as local/regional or distant and PSA screening rate and rate ratios (SRRs) comparing successive survey years by age.

Results  Prostate cancer incidence per 100 000 in men 50 years and older (N = 446 009 in SEER areas) was 534.9 in 2005, 540.8 in 2008, 505.0 in 2010, and 416.2 in 2012; rates began decreasing in 2008 and the largest decrease occurred between 2011 and 2012, from 498.3 (99% CI, 492.8-503.9) to 416.2 (99% CI, 411.2-421.2). The number of men 50 years and older diagnosed with prostate cancer nationwide declined by 33 519, from 213 562 men in 2011 to 180 043 men in 2012. Declines in incidence since 2008 were confined to local/regional-stage disease and were similar across age and race/ethnicity groups. The percentage of men 50 years and older reporting PSA screening in the past 12 months was 36.9% in 2005, 40.6% in 2008, 37.8% in 2010, and 30.8% in 2013. In relative terms, screening rates increased by 10% (SRR, 1.10; 99% CI, 1.01-1.21) between 2005 and 2008 and then decreased by 18% (SRR, 0.82; 99% CI, 0.75-0.89) between 2010 and 2013. Similar screening patterns were found in age subgroups 50 to 74 years and 75 years and older.

Conclusions and Relevance  Both the incidence of early-stage prostate cancer and rates of PSA screening have declined and coincide with 2012 USPSTF recommendation to omit PSA screening from routine primary care for men. Longer follow-up is needed to see whether these decreases are associated with trends in mortality.

Prostate Cancer Incidence and PSA Testing Patterns in Relation to USPSTF Screening Recommendations by Ahmedin Jemal et al.

Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses

Importance  Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed.

Objective  To evaluate if early administration of azithromycin, started prior to the onset of severe LRTI symptoms, in preschool children with recurrent severe LRTIs can prevent the progression of these episodes.

Design, Setting, and Participants  A randomized, double-blind, placebo-controlled, parallel-group trial conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute’s AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by December 2014. Participants were 607 children aged 12 through 71 months with histories of recurrent, severe LRTIs and minimal day-to-day impairment.

Intervention  Participants were randomly assigned to receive azithromycin (12 mg/kg/d for 5 days; n = 307) or matching placebo (n = 300), started early during each predefined RTI (child’s signs or symptoms prior to development of LRTI), based on individualized action plans, over a 12- through 18-month period.

Main Outcomes and Measures  The primary outcome measure was the number of RTIs not progressing to a severe LRTI, measured at the level of the RTI, that would in clinical practice trigger the prescription of oral corticosteroids. Presence of azithromycin-resistant organisms in oropharyngeal samples, along with adverse events, were among the secondary outcome measures.

Results  A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). Azithromycin significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41-0.98], P = .04; absolute risk for first RTI: 0.05 for azithromycin, 0.08 for placebo; risk difference, 0.03 [95% CI, 0.00-0.06]). Induction of azithromycin-resistant organisms and adverse events were infrequently observed.

Conclusions and Relevance  Among young children with histories of recurrent severe LRTIs, the use of azithromycin early during an apparent RTI compared with placebo reduced the likelihood of severe LRTI. More information is needed on the development of antibiotic-resistant pathogens with this strategy.

Trial Registration  clinicaltrials.gov Identifier: NCT01272635

Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses by Leonard B. Bacharier et al.

Maternal vaccination against H1N1 influenza and offspring mortality: population based cohort study and sibling design

Study question What is the mortality in offspring of mothers who had influenza A(H1N1)pdm09 vaccination during pregnancy?

Methods This was a prospective population based cohort study in seven healthcare regions in Sweden based on vaccinations taking place between 2 October 2009 and 26 November 2010. H1N1 vaccination data were linked with pregnancy and birth characteristics and offspring mortality data in 275 500 births (of which 1203 were stillbirths) from 137 886 mothers. Of these offspring, 41 183 had been exposed to vaccination with Pandemrix, a monovalent AS03 adjuvanted H1N1 influenza vaccine, during fetal life. A primary comparison group consisted of pregnancies of women who were not vaccinated during the same calendar period. In a second comparison, non-exposed siblings of infants prenatally exposed to vaccination were used as controls. Cox regression was used to estimate hazard ratios for stillbirth, early neonatal mortality (days 0-6 after birth), and subsequent mortality (beginning on day 7) in vaccinated versus non-vaccinated women, adjusting for mother’s age at delivery, body mass index, parity, smoking, country of birth, and disposable income and for sex of offspring.

Study answer and limitations The results of this study suggest that AS03 adjuvanted H1N1 vaccination during pregnancy does not affect the risk of stillbirth, early neonatal death, or later mortality in the offspring. During follow-up, 1172 stillbirths, 380 early neonatal deaths, and 706 deaths thereafter occurred. Compared with general population controls, this corresponded to adjusted hazard ratios of 0.83 (95% confidence interval 0.65 to 1.04) for stillbirth, 0.71 (0.44 to 1.14) for early neonatal death, and 0.97 (0.69 to 1.36) for later death. When siblings were used as controls, adjusted hazard ratios were 0.88 (0.59 to 1.30) for stillbirth, 0.82 (0.46 to 1.49) for early neonatal death, and 0.78 (0.52 to 1.19) for later death. Limitations of the study include lack of data on miscarriage before gestational week 22, inability to ascertain which mothers had pandemic flu during pregnancy, and lack of data on factors influencing the decision to vaccinate during pregnancy.

What this study adds H1N1 vaccination during pregnancy is not associated with adverse fetal outcome or offspring mortality, including when familial factors are taken into account.

Funding, competing interests, data sharing This project was supported by grants from the Swedish Research Council and the Swedish Council for Working Life and Social Research. NF was employed at the Swedish Medical Product Agency at the time of the study.

Maternal vaccination against H1N1 influenza and offspring mortality: population based cohort study and sibling design by Jonas F Ludvigsson et al.

Antenatal blood pressure for prediction of pre-eclampsia, preterm birth, and small for gestational age babies: development and validation in two general population cohorts

Study question Can routine antenatal blood pressure measurements between 20 and 36 weeks’ gestation contribute to the prediction of pre-eclampsia and its associated adverse outcomes?

Methods This study used repeated antenatal measurements of blood pressure from 12 996 women in the Avon Longitudinal Study of Parents and Children (ALSPAC) to develop prediction models and validated these in 3005 women from the Southampton Women’s Survey (SWS). A model based on maternal early pregnancy characteristics only (BMI, height, age, parity, smoking, existing and previous gestational hypertension and diabetes, and ethnicity) plus initial mean arterial pressure was compared with a model additionally including current mean arterial pressure, a model including the deviation of current mean arterial pressure from a stratified normogram, and a model including both at different gestational ages from 20-36 weeks.

Study answer and limitations The addition of blood pressure measurements from 28 weeks onwards improved prediction models compared with use of early pregnancy risk factors alone, but they contributed little to the prediction of preterm birth or small for gestational age. Though multiple imputation of missing data was used to increase the sample size and minimise selection bias, the validation sample might have been slightly underpowered as the number of cases of pre-eclampsia was just below the recommended 100. Several risk factors were self reported, potentially introducing measurement error, but this reflects how information would be obtained in clinical practice.

What this study adds The addition of routinely collected blood pressure measurements from 28 weeks onwards improves predictive models for pre-eclampsia based on blood pressure in early pregnancy and other characteristics, facilitating a reduction in scheduled antenatal care.

Funding, competing interests, data sharing UK Wellcome Trust, US National Institutes of Health, and UK Medical Research Council. Other funding sources for authors are detailed in the full online paper. With the exceptions of CM-W, HMI, and KMG there were no competing interests.

Antenatal blood pressure for prediction of pre-eclampsia, preterm birth, and small for gestational age babies: development and validation in two general population cohorts by Corrie Macdonald-Wallis et al.

Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis


Antenatal care of women with epilepsy is varied. The association of epilepsy and antiepileptic drug exposure with pregnancy outcomes needs to be quantified to guide management. We did a systematic review and meta-analysis to investigate the association between epilepsy and reproductive outcomes, with or without exposure to antiepileptic drugs.


We searched MEDLINE, Embase, Cochrane, AMED, and CINAHL between Jan 1, 1990, and Jan 21, 2015, with no language or regional restrictions, for observational studies of pregnant women with epilepsy, which assessed the risk of obstetric complications in the antenatal, intrapartum, or postnatal period, and any neonatal complications. We used the Newcastle-Ottawa Scale to assess the methodological quality of the included studies, risk of bias in the selection and comparability of cohorts, and outcome. We assessed the odds of maternal and fetal complications (excluding congenital malformations) by comparing pregnant women with and without epilepsy and undertook subgroup analysis based on antiepileptic drug exposure in women with epilepsy. We summarised the association as odds ratio (OR; 95% CI) using random effects meta-analysis. The PROSPERO ID of this Systematic Review’s protocol is CRD42014007547.


Of 7050 citations identified, 38 studies from low-income and high-income countries met our inclusion criteria (39 articles including 2 837 325 pregnancies). Women with epilepsy versus those without (2 809 984 pregnancies) had increased odds of spontaneous miscarriage (OR 1·54, 95% CI 1·02–2·32;I2=67%), antepartum haemorrhage (1·49, 1·01–2·20; I2=37%), post-partum haemorrhage (1·29, 1·13–1·49; I2=41%), hypertensive disorders (1·37, 1·21–1·55; I2=23%), induction of labour (1·67, 1·31–2·11;I2=64%), caesarean section (1·40, 1·23–1·58; I2=66%), any preterm birth (<37 weeks of gestation; 1·16, 1·01–1·34; I2=64%), and fetal growth restriction (1·26, 1·20–1·33; I2=1%). The odds of early preterm birth, gestational diabetes, fetal death or stillbirth, perinatal death, or admission to neonatal intensive care unit did not differ between women with epilepsy and those without the disorder.


A small but significant association of epilepsy, exposure to antiepileptic drugs, and adverse outcomes exists in pregnancy. This increased risk should be taken into account when counselling women with epilepsy.


EBM CONNECT Collaboration.

Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis by Luz Viale, MD