Steve Morant

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

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.

Influenza but not pneumococcal vaccination protects against all-cause mortality in patients with COPD.

Background: Influenza and pneumococcal vaccination are recommended in patients with chronic obstructive pulmonary disease (COPD). A recent study from Tayside found a reduced risk of all-cause mortality with vaccination in patients with COPD. The Health Improvement Network (THIN) database was used to test this hypothesis in a different data source. Methods: The THIN database was searched for patients with COPD. Vaccination status against Pneumococcus and the annual influenza vaccination status were determined. Mortality rates were calculated in the periods December to March and April to November. Relative risks for the effect of vaccination on all-cause mortality were estimated by Poisson regression, adjusting for age, sex, year and serious co-morbidities. Results: 177 120 patients with COPD (mean age 65 years) were identified, with a mean follow-up of 6.8 years between 1988 and 2006. Vaccination rates against influenza rose from <30% before 1995 to >70% in 2005 in patients aged 60 years or more. The cumulative vaccination rate against pneumonia rose from almost zero to 70% in patients aged 70 years or more over the same period. For all-cause mortality the adjusted relative risks associated with influenza vaccination were 0.59 (95% CI 0.57 to 0.61) during the influenza season and 0.97 (95% CI 0.94 to 1.00) outside the season in patients not vaccinated against pneumonia, and 0.30 (95% CI 0.28 to 0.32) and 0.98 (95% CI 0.96 to 1.11), respectively, in patients vaccinated against pneumonia. The relative risk associated with pneumococcal vaccination was >1 at all times of the year. Conclusions: Influenza but not pneumococcal vaccination was associated with a reduced risk of all-cause mortality in COPD.

A predictive model of hospitalisation and death from chronic obstructive pulmonary disease.

RATIONALE A recent study showed that doctors are excessively pessimistic about the prognosis in patients with COPD and suggested that a simple tool to predict outcome is needed. METHODS In a prospective observational study, 3343 patients with an FEV1<80% of the predicted value and FEV1/FVC<70% were selected from a clinical network of patients screened for COPD in Tayside, Scotland. Data were collected during annual visits on demography, spirometry, smoking history, medical research council (MRC) dyspnoea scale, body mass index (BMI) and other variables. The main outcome measures were hospitalisations and death secondary to COPD. A proportional hazard model was used to identify significant risk factors. RESULTS Increasing age, low BMI, worsening MRC dyspnoea score, decreased FEV1, and prior respiratory or cardiovascular admission hospitalisation were predictors of poor outcome. Influenza vaccination was protective. CONCLUSION We have developed a model that estimates the risk of respiratory hospitalisation and death in patients with COPD.

Biomarker Report from the Phase II Lamotrigine Trial in Secondary Progressive MS – Neurofilament as a Surrogate of Disease Progression

Objective 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. Methods 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. Results 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. Conclusions 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.

Serum neurofilament is associated with progression of brain atrophy and disability in early MS

Objective: To investigate a potential effect of riluzole on serum neurofilaments (Nf) compared to placebo and the relationship between longitudinal clinical and MRI outcomes and serum Nf levels. Methods: Serum samples were obtained from participants enrolled in a randomized double-blind trial of neuroprotection with riluzole vs placebo as an add-on to weekly interferon-β (IFN-β)–1a IM initiated 3 months after randomization. Nf measurements were performed by ELISA and electrochemiluminescence immunoassay. Results: Longitudinal serum samples were available from 22 riluzole and 20 placebo participants over 24 months. There was no observed treatment effect with riluzole. Nf light chain (NfL) levels decreased over time (p = 0.007 at 24 months), whereas the Nf heavy chain was unchanged (p = 0.997). Changes in NfL were correlated with EDSS change (p = 0.009) and neuropsychological outcomes. Brain volume decreased more rapidly in patients with high baseline NfL (p = 0.05 at 12 months and p = 0.008 at 24 months) and this relationship became stronger at 24 months (p = 0.024 for interaction). Higher and increasing NfL predicted higher number of gadolinium-enhancing lesions (p < 0.001 for both). Conclusions: Our findings support the potential value of serum NfL as a marker of neuroaxonal injury in early multiple sclerosis. Its reduction over time could represent regression to the mean, or a possible treatment effect of IFN-β-1a. The association with whole brain atrophy and the formation of acute white matter lesions has relevant implications to use serum NfL as a noninvasive biomarker of the overall consequences of brain damage and ongoing disease activity. ClinicalTrials.gov identifier: NCT00501943.

Investigation into the Value of Trained Glycaemia Alert Dogs to Clients with Type I Diabetes

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.

Spironolactone and risk of incident breast cancer in women older than 55 years: retrospective, matched cohort study

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.

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

Summary 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, 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. 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.

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.

Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2: protocol for a randomised crossover trial to determine optimal treatment for drug-resistant hypertension

Introduction Resistant hypertension is inadequately controlled blood pressure (BP) despite treatment with at least three BP-lowering drugs. A popular hypothesis is that resistant hypertension is due to excessive Na+-retention, and that ‘further diuretic therapy’ will be superior to alternative add-on drugs. Methods and analysis Placebo-controlled, random crossover study of fourth-line treatment when added to standard (A+C+D) triple drug therapy: ACE inhibitor or Angiotensin receptor blocker (A) +Calcium channel blocker (C)+Diuretic (D). Patients (aged 18–79 years) with clinical systolic BP≥140 mm Hg (135 mm Hg in diabetics) and Home BP Monitoring (HBPM) systolic BP average ≥130 mm Hg on treatment for at least 3 months with maximum tolerated doses of A+C+D are randomised to four consecutive randomly allocated 12-week treatment cycles with an α-blocker, β-blocker, spironolactone and placebo. The hierarchical coprimary end point is the difference in HBPM average systolic BP between (in order) spironolactone and placebo, spironolactone and the average of the other two active drugs, spironolactone and each of the other two drugs. A key secondary outcome is to determine whether plasma renin predicts the BP response to the different drugs. A sample size of 346 (allowing 15% dropouts) will confer 90% power to detect a 3 mm Hg HBPM average systolic BP difference between any two drugs. The study can also detect a 6 mm Hg difference in HBPM average systolic BP between each patients best and second-best drug predicted by tertile of plasma renin. Ethics and dissemination The study was initiated in May 2009 and results are expected in 2015. These will provide RCT evidence to support future guideline recommendations for optimal drug treatment of resistant hypertension. Trial registration number Clinicaltrials.gov NCT02369081, EUDract number: 2008-007149-30.