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Context When palliative care patients enter the phase of unconsciousness preceding death, it is standard practice to initiate or continue a subcutaneous infusion of an opioid plus or minus a sedative. The doses are determined somewhat empirically and adjustments are based on clinical assessment and observational measures of sedation and comfort. Following reports that these observational measures could be misleading, this study assesses their validity by comparing them with an objective measure of sedation, the Bispectral Index Score (BIS). Objective The objective of this study was to determine the validity of the Richmond Agitation and Sedation Scale (RASS) and the Patient Comfort Score (PCS) in assessing sedation and comfort in unconscious patients. Methods Forty eligible and consenting patients were monitored from the onset of unconsciousness (unresponsiveness) until death. Measures of sedation (RASS) and comfort (PCS) were made by the attending nurse every four hours. Correlation coefficients examined the relationship between fourth hourly RASS and PCS and time-matched BISs. Results A significant correlation was found between RASS and BIS and PCS and BIS. Sedation and comfort scores were concentrated at the lower end of the respective scales, whereas time-matched BISs were widely scattered with scores ranging from near full awareness to deep sedation. Conclusions Compared with BIS, both RASS and PCS appear to be relatively blunt instruments at the lower end of their respective scales. Due caution should be taken interpreting and making clinical decisions based solely on the RASS and PCS and, by extension, other observational measures of patient comfort and sedation.

Community-acquired pneumonia (CAP) is the second commonest indication for antibiotic use in Australian hospitals and is therefore a frequent target for antimicrobial stewardship. A single-centre prospective study was conducted in a regional referral hospital comparing management of adult patients with CAP before and after an educational intervention. We demonstrated a reduction in duration of therapy and reduced inappropriate use of ceftriaxone-based regimens for non-severe CAP.

Healthcare-associated Clostridium difficile infection (HCA-CDI) remains a major cause of morbidity and mortality in industrialized countries. However, few data exist on the burden of HCA-CDI in multi-site non-metropolitan settings. This study examined the introduction of an antimicrobial stewardship programme (ASP) in relation to HCA-CDI rates, and the effect of HCA-CDI on length of stay (LOS) and hospital costs.A comparative before-and-after intervention study of patients aged ≥16 years with HCA-CDI from December 2010 to April 2016 across the nine hospitals of a non-metropolitan health district in New South Wales, Australia was undertaken. The intervention comprised a multi-site ASP supported by a clinical decision support system, with subsequent introduction of email feedback of HCA-CDI cases to admitting medical officers.HCA-CDI rates, comparative LOS and hospital costs, prior use of antimicrobials and proton pump inhibitors, and appropriateness of CDI treatment.HCA-CDI rates rose from 3.07 to 4.60 cases per 10,000 occupied bed-days pre-intervention, and remained stable at 4 cases per 10,000 occupied bed-days post-intervention (P=0.24). Median LOS (17 vs six days; P0.01) and hospital costs (AU$19,222 vs $7861; P0.01) were significantly greater for HCA-CDI cases (N=91) than for matched controls (N=172). Half of the patients with severe HCA-CDI (4/8) did not receive initial appropriate treatment (oral vancomycin).HCA-CDI placed a significant burden on the regional and rural health service through increased LOS and hospital costs. Interventions targeting HCA-CDI could be employed to consolidate the effects of ASPs.

Background Studies evaluating antimicrobial stewardship programmes (ASPs) supported by computerized clinical decision support systems (CDSSs) have predominantly been conducted in single site metropolitan hospitals. Objectives To examine outcomes of multisite ASP implementation supported by a centrally deployed CDSS. Methods An interrupted time series study was conducted across five hospitals in New South Wales, Australia, from 2010 to 2014. Outcomes analysed were: effect of the intervention on targeted antimicrobial use, antimicrobial costs and healthcare-associated Clostridium difficile infection (HCA-CDI) rates. Infection-related length of stay (LOS) and standardized mortality ratios (SMRs) were also assessed. Results Post-intervention, antimicrobials targeted for increased use rose from 223 to 293 defined daily doses (DDDs)/1000 occupied bed days (OBDs)/month (+32%, P < 0.01). Conversely, antimicrobials targeted for decreased use fell from 254 to 196 DDDs/1000 OBDs/month (-23%; P < 0.01). These effects diminished over time. Antimicrobial costs decreased initially (-AUD$64551/month; P < 0.01), then increased (+AUD$7273/month; P < 0.01). HCA-CDI rates decreased post-intervention (-0.2 cases/10 000 OBDs/month; P < 0.01). Proportional LOS reductions for key infections (respiratory from 4.8 to 4.3 days, P < 0.01; septicaemia 6.8 to 6.1 days, P < 0.01) were similar to background LOS reductions (2.1 to 1.9 days). Similarly, infection-related SMRs (observed/expected deaths) decreased (respiratory from 1.1 to 0.75; septicaemia 1.25 to 0.8; background rate 1.19 to 0.90. Conclusions Implementation of a collaborative multisite ASP supported by a centrally deployed CDSS was associated with changes in targeted antimicrobial use, decreased antimicrobial costs, decreased HCA-CDI rates, and no observable increase in LOS or mortality. Ongoing targeted interventions are suggested to promote sustainability.

Background: The ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) phase 3 clinical trials showed that the adjuvanted recombinant zoster vaccine (RZV) was >= 90% efficacious in preventing herpes zoster in adults. Here we present a comprehensive overview of the safety data from these studies. Methods: Adults aged >= 50 (ZOE-50) and >= 70 (ZOE-70) years were randomly vaccinated with RZV or placebo. Safety analyses were performed on the pooled total vaccinated cohort, consisting of participants receiving at least one dose of RZV or placebo. Solicited and unsolicited adverse events (AEs) were collected for 7 and 30 days after each vaccination, respectively. Serious AEs (SAEs) were collected from the first vaccination until 12 months post-last dose. Fatal AEs, vaccination-related SAEs, and potential immune-mediated diseases (pIMDs) were collected during the entire study period. Results: Safety was evaluated in 14,645 RZV and 14,660 placebo recipients. More RZV than placebo recipients reported unsolicited AEs (50.5% versus 32.0%); the difference was driven by transient injection site and solicited systemic reactions that were generally seen in the first week post-vaccination. The occurrence of overall SAEs (RZV: 10.1%; Placebo: 10.4%), fatal AEs (RZV: 4.3%; Placebo: 4.6%), and pIMDs (RZV: 1.2%; Placebo: 1.4%) was balanced between groups. The occurrence of possible exacerbations of pIMDs was rare and similar between groups. Overall, except for the expected local and systemic symptoms, the safety results were comparable between the RZV and Placebo groups irrespective of participant age, gender, or race. Conclusions: No safety concerns arose, supporting the favorable benefit-risk profile of RZV. (C) 2019 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd.

An unresponsive patient's need and their response to breakthrough medication is determined by clinical assessment and/or observational measures. How closely these methods match the patient's experience is unknown.Determine the efficacy and effectiveness of breakthrough medication in unresponsive patients and the perception of patient comfort made by nurses and family.A prospective study of breakthrough medication in unresponsive patients. The Richmond Agitation-Sedation Scale (RASS) and Patient Comfort Score (PCS) were compared with time-matched Bispectral Index (BIS) Scores. The effects of opioid vs. opioid + benzodiazepine breakthroughs and the relation between synchronous nurse and family measurements of the PCS were evaluated. Analysis of variance and paired t-tests were used for BIS analyses and nonparametric Mann-Whitney tests for RASS and PCS.Significant reductions at 30 and 60 minutes after breakthrough medication were noted for BIS (P 0.0004), RASS (P = 0.043 and 0.004, respectively), and PCS (P 0.0004). A direct comparison of the effect of opioid breakthrough medication vs. opioid plus benzodiazepine revealed no significant difference (BIS, P = 0.512; RASS, P = 0.195; PCS, P = 0.119). Of the 157 synchronous nurse and family measures of patient comfort, families rated patient discomfort significantly higher than nurses (P 0.0004).This study provides additional evidence for the efficacy and effectiveness of breakthrough medication and the merit of observational measures in determining a patient's response. The onset of action is evident at 30 minutes after injection. Family assessment of patient comfort may be more nuanced than that of nurses, and they not uncommonly rate patient discomfort higher than nurses.

INTRODUCTION AND AIMS Alcohol-related morbidity is estimated to range from 10-38% of the presentations to hospital emergency departments. This study aims to investigate the actual management process for alcohol-related presentations in a teaching hospital in Australia. DESIGN AND METHODS Retrospective audit was conducted on the electronic medical records of 210 presentations with a primary or secondary diagnosis of 'alcohol use disorder' at discharge between November 2016 and February 2017. Six key management steps were investigated: identification of alcohol use disorder, documentation, thiamine, alcohol withdrawal assessment, benzodiazepine for alcohol withdrawal and referral to the drug and alcohol consultation liaison service. RESULTS Of all the 210 presentations, 77.1% (162) were identified with alcohol use disorder in the initial assessments; 64.3% (135) were documented with alcohol use history, 49.5% (104) were prescribed with thiamine, 48.1% (101) were assessed with the alcohol withdrawal scale, 41% (86) were prescribed with benzodiazepine for alcohol withdrawal and only 38.6% (81) were referred to the drug and alcohol consultation liaison service. Only 8.6% (18) of the initial presentations were directly related to alcohol. These presentations had a higher completion rate in each of the six steps than those (91.4%, 192) not directly related to alcohol. Only 6.2% (13) were formally screened for alcohol use. DISCUSSION AND CONCLUSIONS The findings suggest a need to improve the alcohol management practice in the hospital. Routine use of an alcohol screening tool can enable early identification of the alcohol use disorder and to improve the management of this problem in the hospital.

Introduction In patients with chronic idiopathic thrombocytopenic purpura (cITP), the platelet count tends to be quite variable and, in the majority of cases, specific therapy is not warranted on a regular basis. However, patients with low platelet count (

Background: Internet-based learning for health professional education is increasing. It offers advantages over traditional learning approaches, as it enables learning to be completed at a time convenient to the user and improves access where facilities are geographically disparate. We developed and implemented the Vancomycin Interactive (VI) e-learning tool to improve knowledge on the clinical use of the antibiotic vancomycin, which is commonly used for treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Objective: The aims of this study were to evaluate the effect of the VI e-learning tool on (1) survey knowledge scores and (2) clinical use of vancomycin among health professionals. Methods: We conducted a comparative pre-post intervention study across the 14 hospitals of two health districts in New South Wales, Australia. A knowledge survey was completed by nurses, doctors, and pharmacists before and after release of a Web-based e-learning tool. Survey scores were compared with those obtained following traditional education in the form of an email intervention. Survey questions related to dosing, administration, and monitoring of vancomycin. Outcome measures were survey knowledge scores among the three health professional groups, vancomycin plasma trough levels, and vancomycin approvals recorded on a computerized clinical decision support system. Results: Survey response rates were low at 26.87% (577/2147) preintervention and 8.24% (177/2147) postintervention. The VI was associated with an increase in knowledge scores (maximum score=5) among nurses (median 2, IQR 1-2 to median 2, IQR 1-3; P

we believe it is essential that all researchers who have direct contact with participants are fully immunised. Disciplines Medicine and Health Sciences Publication Details Townsend, M. L., Grenyer, B. F. S., Yeo, W. & Wright, I. (2016). Immunisation for medical researchers: an ethical and practical imperative. Medical Journal of Australia, 204 (7), 263-263. This journal article is available at Research Online: http://ro.uow.edu.au/ihmri/775 Immunisation for medical researchers: an ethical and practical imperative Michelle L Townsend PhD Brin FS Grenyer BA(HONS), MSc, PhD? Wilfred Yeo MB ChB, MD, FRACP Ian Wright FRACP 1 School of Psychology and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong. 2 Graduate School of Medicine and Illawarra Health and Medical Research Institute University of Wollongong, Wollongong. doi: 10.5694/mja15.01179 Participants in medical research are the most valuable resource within health research, and their wellbeing must be regarded as paramount. Australia’s national statement on ethical conduct in human research1 establishes that the burden is on researchers to safeguard the health, wellbeing and autonomy of their research participants. We argue that additional guidance is required in an area that has not been widely considered in the ethical research literature and policy: immunisation coverage of the research team. It is acknowledged that health care workers with immunisation‐preventable disease infect their patients.2,3 There is no reason to believe that researchers are exempt from transmitting these diseases to their participants. There are national guidelines4 that provide evidence‐based recommendations on immunisation for people at occupational risk, but this guidance does not specifically refer to researchers. We present a case study to illustrate the issue. We undertook a cross‐generational longitudinal study examining environmental, lifestyle and genetic factors influencing health and wellbeing across the lifespan. The study, based at a medical research institute, involved recruiting pregnant women in collaboration with the local health district. University researchers sought honorary appointments for recruitment and data collection in the hospital setting, with the expectation that we would be required to prove immunisation currency according to relevant state health policy.5 When the resultant honorary researcher appointment applications were approved we were not required to demonstrate any immunisation status. There may be several reasons for this: first that individuals classifying risk may interpret the rules differently; and second, employment status in clinical research studies with multiple researchers from different organisations is complex. The study researchers reviewed the university immunisation guidelines and found that those on clinical placements in state health facilities required immunisation coverage, but for all others, including researchers, immunisation was voluntary. After careful consideration, we decided that ensuring the research team was fully immunised was the most ethical way to approach our research. In consultation with an infection control specialist at the local health district, we agreed on several immunisations or evidence of serological immunity. To fulfil our responsibilities as ethical researchers, we believe it is essential that all researchers with direct contact with participants be fully immunised, using national guidelines, against relevant diseases. The prevention of avoidable harm would appear to be an ethical imperative, but we can find no consistent guidance in this area for researchers at a national or international level. We suggest that it is appropriate for the National Health and Medical Research Council to consider guidance on immunisation coverage of researchers with direct contact with participants, rather than leaving it to individual research ethics committees.

Statins are increasingly being used for the treatment of a variety of conditions beyond their original indication for cholesterol lowering. We previously reported that simvastatin affected the dopaminergic system in the rat brain. This study aims to investigate regional changes of muscarinic M1/4 receptors in the rat brain after 4-week administration of simvastatin (1 or 10 mg/kg/day). M1/4 receptor distribution and alterations in the post-mortem rat brain were detected by [(3)H]pirenzepine binding autoradiography. Simvastatin (1 mg/kg/day) increased [(3)H]pirenzepine binding, predominantly in the prefrontal cortex (171%, P0.001), primary motor cortex (153%, P=0.001), cingulate cortex (109%, P0.001), hippocampus (138%, P0.001), caudate putamen (122%, P=0.002) and nucleus accumbens (170%, P0.001) compared with controls; while lower but still significant increases of [(3)H]pirenzepine binding were observed in the examined regions following simvastatin (10 mg/kg/day) treatment. Our results also provide strong evidence that chronic simvastatin administration, especially at a low dosage, up-regulates M1/4 receptor binding, which is likely to be independent of its muscarinic agonist-like effect. Alterations in [(3)H]pirenzepine binding in the examined brain areas may represent the specific regions that mediate the clinical effects of simvastatin treatment on cognition and memory via the muscarinic cholinergic system. These findings contribute to a better understanding of the critical roles of simvastatin in treating neurodegenerative disorders, via muscarinic receptors.

The prostanoid, PGE2, is known to inhibit human lung mast cell activity. The aim of the present study was to characterize the EP receptor that mediates this effect. PGE2 (pEC50, 5.8±0.1) inhibited the IgE-mediated release of histamine from mast cells in a concentration-dependent manner. Alternative EP receptor agonists were studied. The EP2-selective agonist, butaprost (pEC50, 5.2±0.2), was an effective inhibitor of mediator release whereas the EP1/EP3 receptor agonist, sulprostone, and the EP1-selective agonist, 17-phenyl-trinor-PGE2, were ineffective. The DP agonist PGD2, the FP agonist PGF2α, the IP agonist iloprost and the TP agonist U-46619 were ineffective inhibitors of IgE-mediated histamine release from mast cells. PGE2 induced a concentration-dependent increase in intracellular cAMP levels in mast cells. The effects of the EP1/EP2 receptor antagonist, AH6809, and the EP4 receptor antagonist, AH23848, on the PGE2-mediated inhibition of histamine release were determined. AH6809 (pKB, 5.6±0.1) caused a modest rightward shift in the PGE2 concentration–response curve, whereas AH23848 was ineffective. Long-term (24 h) incubation of mast cells with either PGE2 or butaprost (EP2 agonist), but not sulprostone (EP1/EP3 agonist), caused a significant reduction in the subsequent ability of PGE2 to inhibit histamine release. Collectively, these data suggest that PGE2 mediates effects on human lung mast cells by interacting with EP2 receptors. British Journal of Pharmacology (2006) 147, 707–713. doi:10.1038/sj.bjp.0706664

The large number of medications available has complicated the learning of drug therapy for medical students at a time when pharmacology training has been substantially reduced. Attempts to remedy this include: improving the pharmaco-therapeutics curriculum; interactive web-based learning and students developing a personal formulary. The approach adopted by the University of Wollongong Medical School is to integrate clinical pharmacology throughout the course, with the Student Preferred-drugs Formulary linking pharmacology and common diseases. Evidence from other countries suggests this should enhance prescribing by medical graduates.

Background The recombinant herpes zoster (HZ) subunit vaccine (HZ/su) has shown efficacy against HZ in adults ≥50 and ≥70 years of age (YOA), in two pivotal Phase III clinical trials (NCT01165177, NCT01165229). A pooled safety analysis of data from these two efficacy studies was performed, including a comparative analysis on HZ/su vs. placebo groups, to provide a comprehensive understanding of the HZ/su safety profile. Methods Two pivotal, randomized, placebo-controlled Phase III studies, assessed the efficacy, reactogenicity and safety of HZ/su, administered intramuscularly according to a 0, 2-month schedule. Solicited and unsolicited adverse events (AEs) were collected for 7 and 30 days after each dose, respectively; serious AEs (SAEs) for 1 year after last dose; fatal and related SAEs and potential immune-mediated diseases (pIMDs) during the entire study period. Reactogenicity was assessed in a subset of participants; safety was assessed in all vaccinated participants. Results 29,305 participants ≥50 YOA (HZ/su: 14,645; placebo: 14,660) were included in the pooled analysis. HZ/su was more reactogenic than placebo. Local reactions were mostly mild to moderate in intensity and transient (median duration = 3 days); the percentages of participants reporting SAEs, fatal SAEs and pIMDs were similar in both groups, at 30 days and 1 year after last dose (Figures 1 and 2). Percentages of fatal SAEs ranged between 4.3% (95% Confidence Interval [CI]: 4.0–4.7) and 4.6% (95% CI: 4.3–5.0) and pIMDs between 1.2% (95% CI: 1.1–1.4) and 1.4% (95% CI: 1.2–1.6), in HZ/su and placebo groups, respectively. In both groups, the most frequent causes of death were neoplasms, cardiac disorders, and respiratory tract infections and infestations, and most frequent pIMDs were polymyalgia rheumatica, rheumatoid arthritis and psoriasis. Conclusion No safety concern was identified. Together with the high efficacy against HZ (97.2% [95% CI: 93.7–99.0],1 91.3% [95% CI: 86.8–94.5]2), the safety data supports a favorable benefit/risk profile of HZ/su in participants ≥50 YOA. Funding GlaxoSmithKline Biologicals SA Disclosures M. López-Fauqued, GSK Biologicals’: Employee, Salary; L. Campora, GSK Biologicals’: Employee, Salary; F. Delannois, GSK Vaccines: Employee, Salary; M. El Idrissi, GSK Vaccines: Employee, Salary; E. Ledent, GSK Vaccines: Employee, Salary; J. Diez-Domingo, GSK Vaccines: Consultant and Investigator, Educational support and Research grant; J. McElhaney, GSK Vaccines: Scientific Advisor, Speaker honorarium; S. McNeil, GSK/Merck: Grant Investigator, Investigator and Scientific Advisor, Consulting fee, Grant recipient, Research grant, Research support and Speaker honorarium; F. De Looze, GSK Vaccines: Investigator and Research Contractor, Research support; F. Tavares Da Silva, GSK Vaccines: Employee, restricted shares and Salary

Background: Traditional approaches to health professional education are being challenged by increased clinical demands and decreased available time. Web-based e-learning tools offer a convenient and effective method of delivering education, particularly across multiple health care facilities. The effectiveness of this model for health professional education needs to be explored in context. Objectives: The study aimed to (1) determine health professionals’ experience and knowledge of clinical use of vancomycin, an antibiotic used for treatment of serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and (2) describe the design and implementation of a Web-based e-learning tool created to improve knowledge in this area. Methods: We conducted a study on the design and implementation of a video-enhanced, Web-based e-learning tool between April 2014 and January 2016. A Web-based survey was developed to determine prior experience and knowledge of vancomycin use among nurses, doctors, and pharmacists. The Vancomycin Interactive (VI) involved a series of video clips interspersed with question and answer scenarios, where a correct response allowed for progression. Dramatic tension and humor were used as tools to engage users. Health professionals’ knowledge of clinical vancomycin use was obtained from website data; qualitative participant feedback was also collected. Results: From the 577 knowledge survey responses, pharmacists (n=70) answered the greatest number of questions correctly (median score 4/5), followed by doctors (n=271; 3/5) and nurses (n=236; 2/5; P

Aims To determine the effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes and to compare their inhibitory potencies and CYP3A4 inactivation parameters with those reported previously for mibefradil. Methods Simvastatin metabolism was investigated in human liver microsomes in the presence and absence of verapamil or diltiazem (0.1–250 µm). Kinetics of CYP3A4 inactivation by verapamil and diltiazem were determined using testosterone as the substrate. Results When verapamil was coincubated with simvastatin, IC50 values ranged from 23 to 26 µm for all major metabolites. The IC50 values ranged from 4.8 to 5.6 µm on preincubation of verapamil for 30 min in the presence of an NADPH-generating system. Corresponding IC50 values for diltiazem ranged from110–127 µm and from 21–27 µm, respectively. Verapamil and diltiazem inhibited testosterone 6β-hydroxylation in a time- and concentration-dependent manner, key features of mechanism-based inactivation. Values for the inactivation parameters kinact and KI were 0.15 ± 0.04 min−1 (mean ± s.d.) and 2.9 ± 0.6 µm, respectively, for verapamil and 0.07 ± 0.01 min−1 and 3.3 ± 1.5 µm, respectively, for diltiazem. Conclusions The IC50 values for coincubation of verapamil and diltiazem were 46- and 220-fold higher, respectively, than those reported previously for mibefradil, and 16- and 71-fold higher, respectively, for preincubation. Thus, the results of this study suggest that verapamil and diltiazem are less likely than mibefradil to cause acute drug interactions with simvastatin in vivo. However, verapamil and diltiazem are moderate mechanism-based inhibitors of CYP3A4 and therefore may still cause significant inhibition of simvastatin metabolism in vivo during chronic therapy.

To examine the accuracy of a new version of the Sheffield table designed to aid decisions on lipids screening and detect thresholds for risk of coronary heart disease needed to implement current guidelines for primary prevention of cardiovascular disease.Comparison of decisions made on the basis of the table with absolute risk of coronary heart disease or cardiovascular disease calculated by the Framingham risk function. The decisions related to statin treatment when coronary risk is/=30% over 10 years; aspirin treatment when the risk is/=15% over 10 years; and the treatment of mild hypertension when the cardiovascular risk is/=20% over 10 years.The table is designed for use in general practice.Random sample of 1000 people aged 35-64 years from the 1995 Scottish health survey.Sensitivity, specificity, and positive and negative predictive values of the table.13% of people had a coronary risk of/=15%, and 2. 2% a risk of/=30%, over 10 years. 22% had mild hypertension (systolic blood pressure 140-159 mm Hg). The table indicated lipids screening for everyone with a coronary risk of/=15% over 10 years, for 95% of people with a ratio of total cholesterol to high density lipoprotein cholesterol of/=8.0, but for50% with a coronary risk of5% over 10 years. Sensitivity and specificity were 97% and 95% respectively for a coronary risk of/=15% over 10 years; 82% and 99% for a coronary risk of/=30% over 10 years; and 88% and 90% for a cardiovascular risk of/=20% over 10 years in mild hypertension.The table identifies all high risk people for lipids screening, reduces screening of low risk people by more than half, and ensures that treatments are prescribed appropriately to those at high risk, while avoiding inappropriate treatment of people at low risk.

Dietary advice for the reduction of coronary heart disease events emphasizes the importance of a low-fat diet and advice on the consumption of oily fish may also be given. This report reviews the evidence linking fish consumption with coronary risk. On the basis of available evidence, a target of two to three portions of oily fish per week (200–400 g, 7–14 oz) is considered reasonable, particularly for secondary prevention. For those who cannot achieve the suggested dietary intake of oily fish, the partial or complete substitution of fish oil supplements may be appropriate. A range of suitable types of fish oil supplements is given, but an awareness of the potential adverse effects of fish oil supplementation is considered important. Further studies are needed to define the role of fish intake in coronary heart disease.

After myocardial infarction, beta-blockers, aspirin and (in selected patients) ACE inhibitors all reduce substantially the risk of further myocardial infarction or coronary death. With regard to life-style changes, giving up cigarette smoking reduces coronary risk by about 50%. Weight reduction and regular exercise are advised, although the effect of these measures on prognosis is uncertain. Recently, two major trials, the Scandinavian Simvastatin and West of Scotland Pravastatin studies, have radically changed ordinary medical practice. In these trials HMG CoA reductase inhibitor (statin) treatment reduced coronary events by 30–40%, reduced all-cause mortality, and proved safe and well-tolerated. The accepted policy now is to treat all patients with coronary heart disease, who have a cholesterol concentration 5.5 mmol/l or higher, with a statin. Where does this leave cholesterol-lowering dietary advice in secondary prevention? The benefits of statin treatment were attained by reducing serum cholesterol by an average of 25%. Diet change rarely attains such a fall in cholesterol and should therefore be used only as an adjunct to drug therapy. When recommending a lipid-lowering diet there is a danger that patients may be denied highly-effective drug treatment because of the «threshold» effect. A decision on the need for cholesterol reduction should be made before diet change is advised. Once the decision is made the target is a 25% cholesterol reduction, which will require drug therapy in addition to diet changes.

Summary When used for the secondary prevention of coronary heart disease, treatment with an inhibitor of hydroxymethylglutaryl-coenzyme-A reductase results in worthwhile benefit that clearly exceeds any risk in patients whose risk of coronary death is 1·5% or more per year. This evidence can be extrapolated logically to primary prevention of coronary disease provided that treatment is targeted at those with similar or higher risk. We present a table that refines previously proposed methods of risk prediction. The table identifies subjects who have the specified degree of coronary risk; shows the serum cholesterol concentration that confers that degree of risk in the individual; and identifies subjects who will not have this degree of risk, irrespective of their cholesterol concentration. It is simple enough for use in ordinary practice. The table highlights the predominant effect of age on coronary risk; a person who is free of vascular disease and younger than 52 years is unlikely to have the specified degree of risk. Even in older people (60-70 years) several risk factors are generally required to attain this degree of risk. Some people are candidates for lipid-lowering drug treatment with serum cholesterol as low as 5·5 mmol/L, whereas others with cholesterol as high as 9·0 mmol/L are not. Although cholesterol lowering is a powerful method for preventing coronary events in people at high risk, cholesterol measurement by itself is not a good way to identify those with high coronary risk. The method can be adapted readily to target a different level of coronary risk as new evidence on the benefit and risk of treatment becomes available.

The beta adrenergic agonist isoprenaline inhibited the IgE-triggered release of the preformed mediator histamine from human lung mast cells (HLMC) in a dose-dependent fashion. After prolonged (> or = 4 h) preexposure of HLMC to isoprenaline, there was a subsequent diminution in the effectiveness of a second exposure of isoprenaline to inhibit the release of histamine from activated HLMC. This induced hyporesponsiveness to isoprenaline was both concentration and time dependent. Although maximal levels of desensitization were obtained after an initial prolonged (14-h) preincubation with a high (10(-5) M) concentration of isoprenaline, exposure of HLMC for a shorter (4-h) time period with a lower (3 x 10(-7) M) concentration of isoprenaline was also effective at inducing a functional desensitization to isoprenaline. The inhibitory activity of the beta 2 agonist fenoterol was attenuated after a prolonged (14-h) pretreatment step with isoprenaline (10(-5)M), whereas the inhibitory properties of other adenylate cyclase activators, prostaglandin E2 and forskolin, were not affected appreciably. Prolonged (12-h) exposure of HLMC to the beta agonists fenoterol, salbutamol, and terbutaline also induced hyporesponsive states of beta agonists, qualitatively similar to that obtained with isoprenaline. The beta receptor antagonist propranolol, if coincubated with isoprenaline during the prolonged pretreatment step, protected against the subsequent refractoriness of the HLMC to isoprenaline. The glucocorticoid dexamethasone failed to prevent the isoprenaline-induced functional desensitization. In total, these results indicate that prolonged exposure of HLMC to beta agonists induces a state of selective hyporesponsiveness to agonists that act at beta adrenoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

1. In nine hypertensive patients with enalapril-induced cough the effect of altering the dose of enalapril on subjective cough and the cough response to inhaled capsaicin was examined in a random single-blind balanced cross-over study. They received three doses of enalapril, each for 3 weeks; the dose at entry (mean 10 mg daily); double this dose (mean 20 mg daily); and half this dose (mean 5 mg daily). 2. The cough response to inhaled capsaicin was also measured in two control groups: hypertensive patients on long-term enalapril treatment with no cough (n = 18), and hypertensive patients taking nifedipine (n = 17). 3. In patients with enalapril-induced cough there were significant dose-responses for enalapril as regards severity of cough (P < 0.05) and night time waking by cough (P < 0.05), but not for frequency of cough. Although the cough was less severe (P < 0.02) and caused less night time waking (P < 0.03) on the lowest dose of enalapril (mean 5 mg daily) it did not disappear completely in any patient. 4. The sensitivity to inhaled capsaicin did not differ significantly on the three doses of enalapril. The relative potency of capsaicin on enalapril 20 mg compared with enalapril 5 mg was 1.0 (95% CI 0.4-2.2). The wide confidence limits indicate that an important dose-dependent shift in capsaicin sensitivity is not excluded. 5. The sensitivity to inhaled capsaicin differed significantly between patients with enalapril-induced cough and both control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The 4-hydroxylation of propranolol by rat and human liver microsomes is associated with formation of a chemically reactive species which binds irreversibly to cytochrome P4502D6 (CYP2D6) destroying its catalytic function. Therefore, the effect of propranolol treatment (80 mg twice daily) on debrisoquine phenotype was examined, to see if it resulted in phenocopying in vivo. The role of 4-hydroxypropranolol (4OHP) in the inhibition of CYP2D6 activity was also studied using microsomes from yeast expressing CYP2D6 and from human livers; metoprolol was used as the CYP2D6 substrate. 2. Although a significant effect on apparent oxidation phenotype was demonstrated, the absolute change in the urinary debrisoquine/4-hydroxydebrisoquine ratio (D/4HD) was small, such that no extensive metaboliser who received propranolol treatment was reclassified as a poor metaboliser. The in vitro studies indicated that 4OHP is a potent inhibitor of metoprolol metabolism (Ki approximately 1 microM). This inhibitory effect was enhanced when 4OHP was pre-incubated in the presence of a NADPH generating system and human liver microsomes. The effect was decreased significantly when reduced glutathione was added to the pre-incubation mixture. Metabolism of 4OHP occurred when incubated with human liver microsomes in the presence of a NADPH generating system and irrespective of CYP2D6 phenotype; yeast expressing CYP2D6 did not metabolise 4OHP. 3. We conclude that, although treatment with propranolol 80 mg twice daily significantly decreases the catalytic function of CYP2D6, the inhibition is insufficient to result in phenocopying. The reactive intermediate produced by further metabolism of 4OHP is probably scavenged effectively in vivo by glutathione and other nucleophiles.

Hypokalaemia, hyperuricaemia, hypomagnesaemia and alterations to lipid and glucose metabolism undoubtedly occur with loop and thiazide diuretic treatment. Many of the metabolic effects induced by thiazide diuretics, however, can be limited by the use of low doses. Apart from precipitation of gout and worsening control of diabetes the clinical importance of these changes is slight. In hypertensive patients treated with diuretics, long-term outcome trials have shown significant benefit in terms of reduction in stroke and coronary events. Diuretics should therefore remain first-line treatment for all patients with heart failure, and in patients with hypertension except those with diabetes or gout.

There is a definite relation of diuretic treatment to impaired glucose tolerance and biochemical diabetes, and a probable relation to insulin resistance. The effect of diuretics on glucose tolerance is dose-related. Spironolactone does not impair glucose tolerance even at high dosage, but apparent differences between other diuretics may well be due to comparison at doses which are not equivalent. Diuretic-induced changes in carbohydrate metabolism are not conclusively related to altered potassium homeostasis, and impaired glucose tolerance occurs when relatively low doses of thiazide are combined with potassium-sparing agents. The effect of diuretics on glucose tolerance is largely and possibly wholly reversible. These disturbances of carbohydrate homeostasis have been detected by detailed biochemical testing, and their clinical importance is uncertain. In established diabetes, diuretics have a rapid and substantial adverse effect on metabolic control. In non-diabetic subjects diuretics may rarely cause or trigger a serious hyperosmolar non-ketotic diabetic syndrome. This apart, it is not known whether the metabolic changes cause clinical diabetes or lead to microvascular complications in the long-term. It is now established that biochemical diabetes, glucose intolerance and insulin resistance probably do not increase the risk of coronary heart disease in treated hypertensive patients. Diuretics should be avoided in patients with diabetes, otherwise they remain an excellent choice for first-line antihypertensive therapy.

The rapid-sequence intravenous urogram (IVU) has tended to fall from favour for investigating hypertension because of its perceived imprecision for detecting renovascular disease. However, no study has examined the value of the IVU as a screening test in appropriately selected patients. We have analysed the diagnostic yield of the rapid-sequence IVU in hypertensive patients selected for features suggesting renal or renovascular disease in a retrospective review of case records from a hypertension clinic. The IVU was abnormal in 27% (95% CI 21-32%) of 241 consecutive patients. The most common abnormalities were chronic pyelonephritis (6%); proven renovascular disease (5%); stone (4%); possible renovascular disease and simple cyst (each 3%); hydronephrosis (2%); and tumour and active tuberculosis (each 1%). The IVU led to intervention aiming to correct hypertension in 5% (95% CI 2-8%) of patients, and revealed an abnormality needing intervention in its own right in 4% (95% CI 2-6%). The IVU led to unnecessary invasive investigation in 3% of cases. Individual abnormalities could not be predicted from the clinical or laboratory features. The initial investigation in hypertensive patients with suspected renal or renovascular disease should be a general purpose test able to detect a wide range of abnormalities. The rapid-sequence IVU is the only single test capable of satisfying this requirement. In patients with features suggesting renovascular disease, a normal rapid-sequence IVU excludes renovascular disease with 93% probability, but is an imperfect screening test since it fails to diagnose about 20% of cases. Renal arteriography should be done despite a normal IVU when it is essential to exclude renovascular disease.

OBJECTIVE--To evaluate the long term efficacy of diets in lowering serum cholesterol concentration. DESIGN--Descriptive overview of 16 published controlled trials of six months9 duration or longer. SETTING--Trials had been conducted in hospital clinics (6), industry (3), mental hospitals or institutions (3), and in general populations (4). PATIENTS--Trials had been conducted in high risk subjects (5), in unselected healthy subjects (6), or for secondary prevention in patients with coronary heart disease (5). Women were included in only four trials. INTERVENTIONS--Diets equivalent to the step 1 diet were employed in eight trials, with individual intervention by dietitians (3) or occupational physicians (2) or with population advice (3). Intensive diets which were more rigorous than the step 2 diet were employed in eight trials. MAIN OUTCOME MEASURES--Net change in serum total cholesterol concentration in subjects receiving treatment with diet compared with values in control subjects after six months to 10 years. RESULTS--In five trials with the step 1 diet as individual intervention the net reduction in serum cholesterol concentration ranged from 0% to 4.0% over six months to six years. In trials with population education reductions in cholesterol concentrations were 0.6-2.0% over five to 10 years. When population and individual dietary advice were combined changes in cholesterol concentration ranged from a fall of 2.1% to a rise of 1.0% over four to 10 years. Diets more intensive than the step 2 diet reduced serum cholesterol concentration by 13% over five years in selected high risk men in the population; by 6.5-15.1% over two to five years in hospital outpatients; and by 12.8-15.5% over one to four and a half years in patients in institutions. CONCLUSIONS--The response to a step 1 diet is too small to have any value in the clinical management of adults with serum cholesterol concentrations above 6.5 mmol/l. Current guidelines recommend screening of serum cholesterol concentration in healthy subjects, followed by treatment with a step 1 diet. The guidelines should be reviewed to provide a more realistic estimate of the effect of a step 1 diet and of the likely need for lipid lowering drugs.

The prostanoid, PGE2, is known to inhibit human lung mast cell activity. The aim of the present study was to characterize the EP receptor that mediates this effect. PGE2 (pEC(50), 5.8+/-0.1) inhibited the IgE-mediated release of histamine from mast cells in a concentration-dependent manner. Alternative EP receptor agonists were studied. The EP2-selective agonist, butaprost (pEC50, 5.2+/-0.2), was an effective inhibitor of mediator release whereas the EP1/EP3 receptor agonist, sulprostone, and the EP1-selective agonist, 17-phenyl-trinor-PGE2, were ineffective. The DP agonist PGD2, the FP agonist PGF(2alpha), the IP agonist iloprost and the TP agonist U-46619 were ineffective inhibitors of IgE-mediated histamine release from mast cells. PGE2 induced a concentration-dependent increase in intracellular cAMP levels in mast cells. The effects of the EP1/EP2 receptor antagonist, AH6809, and the EP4 receptor antagonist, AH23848, on the PGE2-mediated inhibition of histamine release were determined. AH6809 (pK(B), 5.6+/-0.1) caused a modest rightward shift in the PGE2 concentration-response curve, whereas AH23848 was ineffective. Long-term (24 h) incubation of mast cells with either PGE2 or butaprost (EP2 agonist), but not sulprostone (EP1/EP3 agonist), caused a significant reduction in the subsequent ability of PGE2 to inhibit histamine release. Collectively, these data suggest that PGE2 mediates effects on human lung mast cells by interacting with EP2 receptors.

BACKGROUND British guidelines recommend treatment for mild hypertension at a cardiovascular (CVD) risk threshold of 20% over 10 years. However, treatment is targeted at the equivalent coronary (CHD) risk of 15% over 10 years. We examined the relationship between CHD and CVD risk in men and women with mild hypertension and assessed the accuracy of using a 10-year CHD risk threshold of 15% to identify patients at a 10-year CVD risk > or = 20%. DESIGN Cross-sectional survey of England in 1998. METHODS We identified 5588 subjects aged 35-74 years free of cardiovascular disease with complete data for risk assessment. Of these, 1364 (24.4%) had mild hypertension (systolic pressure 140-159 mmHg or diastolic pressure 90-99 mmHg). The Framingham functions were used to estimate CHD and CVD event risk for each individual. RESULTS At a 10-year CHD risk of 15%, the corresponding 10-year CVD risk for men and women, respectively was 20% and 21% in those aged or = 55 years. Using a 10-year CHD risk threshold of 15% to identify patients at a 10-year CVD risk > or = 20% had high specificity (>96%) in all four groups. For men and women respectively, the sensitivity was 73% (62-84%) and 62% (35-88%) in younger subjects, and 89% (85-93%) and 47% (38-56%) in older subjects. CONCLUSION Using a 10-year CHD risk of 15% to target patients at a 10-year CVD risk > or = 20% was reasonably accurate for men but missed about 50% of women eligible for antihypertensive treatment.

Objectives To examine the risk of cardiovascular disease associated with high-normal blood pressure in English adults and estimate the proportion of these individuals who are at high cardiovascular risk. Design and Setting Cross-sectional survey of England in 1998. Participants Nationally representative sample of 12 341 individuals aged 18-80 years living in private households in England. Main outcome measure Percentage of individuals with high-normal blood pressure who have cardiovascular disease, diabetes mellitus or a 10-year cardiovascular event risk of at least 20%. Results Of the 12 341 participants, 2413 (19.6%) had high-normal blood pressure. About 5.3% of those aged 18-80 years with high-normal blood pressure had cardiovascular disease or diabetes, and a further 7.6% were at a predicted cardiovascular event risk of at least 20% over 10 years. The mean predicted risk was 8.7% for men and 6.3% for women in the high-normal blood pressure category. The majority of men aged 61-80 years were at high cardiovascular risk. On average, men and women with high-normal blood pressure had a greater incidence of cardiovascular disease and diabetes mellitus, and a greater predicted mean cardiovascular risk than those with normal blood pressure. Extending antihypertensive treatment to individuals with high-normal blood pressure who are at high cardiovascular risk would involve treating an additional 2.5% of the English population aged 18-80 years. Conclusion These findings support the view that individuals with high-normal blood pressure at high risk for cardiovascular disease should be targeted for blood pressure-lowering treatment.

Background There is broad agreement that statin treatment should be targeted at absolute coronary heart disease (CHD) risk but no consensus on the level of risk to target. We have examined the implications of adopting three different treatment policies for the management of hypertensive patients in the UK using data from treated hypertensives aged 35-69 years included in the Health Survey for England (1993). Methods We calculated the proportion of hypertensive patients with existing atherosclerotic cardiovascular disease requiring statin treatment for secondary prevention of CHD. For those without atherosclerotic cardiovascular disease (primary prevention), we estimated CHD risk from the Framingham equation and examined the proportion with CHD risk exceeding thresholds of 4.5, 3 and 1.5% per year. Results Twenty-one percent of treated hypertensives would require statin treatment for secondary prevention of CHD. When the CHD event threshold for statin treatment was set at > or =4.5% per year [equivalent to a number needed to treat (NNT) in 5 years of 13] a further 0.6% of hypertensive patients were identified for treatment; at a threshold of 3.0% per year (NNT = 20) 5.5% of patients were identified for primary prevention; and at a threshold of 1.5% per year (NNT = 40) 28.5% of patients were identified for primary prevention. Conclusions Those needing secondary prevention are first priority for statins and 21% of hypertensive patients will require treatment Formulation of guidelines for primary prevention should take into account the NNT; the proportion of patients targeted for treatment; the cost-effectiveness and the total cost of treatment. Current British guidance will entail treating an additional 5.5% of hypertensive patients for primary prevention and therefore 27% of hypertensive patients.

Previous studies of the association between hypertension and panic disorder were uncontrolled or involved small numbers of patients.We compared the prevalence of panic disorder and panic attacks in 351 patients with documented hypertension who were randomly selected from all hypertensive patients registered in one primary care practice with age- and gender-matched normotensive patients from the same practice and with hypertensive patients attending a hospital clinic. All three groups completed questionnaires for panic disorder based on standard criteria, as well as the Hospital Anxiety and Depression scale.The prevalence of current (previous 6 months) panic attacks was significantly greater in primary care patients with hypertension (17%, P0.05) and hospital-based hypertensive patients (19%, P0.01) than in normotensive patients (11%). Similar results were seen for lifetime panic attacks (35% versus 39% versus 22%; both P for comparisons with normotensive patients0.001). The prevalence of panic disorder was significantly greater in primary care patients with hypertension (13%) than normotensive patients (8%, P0.05). Anxiety scores were significantly higher in both hypertensive groups than in normotensive patients. Depression scores were significantly higher in hospital-based hypertensive patients than in the other two groups. The reported diagnosis of hypertension antedated the onset of panic attacks in a large majority of patients (P0.01).Physicians caring for patients with hypertension should be aware of the significantly greater prevalence of panic attacks in these patients.

OBJECTIVES—To estimate the cost effectiveness of statin treatment in preventing coronary heart disease (CHD) and to examine the effect of the CHD risk level targeted and the cost of statins on the cost effectiveness of treatment. DESIGN—Cohort life table method using data from outcome trials. MAIN OUTCOME MEASURES—The cost per life year gained for lifelong statin treatment at annual CHD event risks of 4.5% (secondary prevention) and 3.0%, 2.0%, and 1.5% (all primary prevention), with the cost of statins varied from £100 to £800 per year. RESULTS—The costs per life year gained according to annual CHD event risk were: for 4.5%, £5100; 3.0%, £8200; 2.0%, £10 700; and 1.5%, £12 500. Reducing the cost of statins increases cost effectiveness, and narrows the difference in cost effectiveness across the range of CHD event risks. CONCLUSIONS—At current prices statin treatment for secondary prevention, and for primary prevention at a CHD event risk 3.0% per year, is as cost effective as many treatments in wide use. Primary prevention at lower CHD event risks (

This article examines the rationale for the differences in the guidelines for hypertension management of four national or international bodies: the Joint National Committee (JNC-V), The World Health Organization/International Society of Hypertension (WHO-ISH), the British Hypertension Society (BHS), and the New Zealand guidelines. These guidelines agree on many aspects of management, but differ on two very important points—the drugs of first choice for hypertension, and the indications for drug treatment of uncomplicated mild hypertension. JNC-V recommends treatment routinely of all people with a sustained blood pressure of 140/90 mm Hg, whereas the BHS guidelines advise treatment routinely at 160/100 mm Hg. Such differences in the threshold for treatment have a major impact on the proportion of the adult population to be treated, and on the benefit from treatment. JNC-V was heavily influenced by the Hypertension Detection and Follow-up Program (HDFP), which appeared to show a large benefit from the treatment of uncomplicated mild hypertension, whereas the BHS guidelines were influenced by the Medical Research Council (MRC) Trial, which showed a very small benefit. However, the apparent differences in absolute benefit between these, and other, randomized controlled trials is related entirely to differences in the absolute cardiovascular risk of the populations studied. In populations and in individual patients the benefit from antihypertensive treatment is determined by the absolute cardiovascular risk. Blood pressure by itself is a very weak predictor of risk or benefit from treatment. In uncomplicated mild hypertension the need for drug therapy should be based on the absolute risk of cardiovascular complications, estimated by considering age, sex, serum cholesterol level, diabetes mellitus status, and smoking habits, in addition to blood pressure. Doctors cannot estimate absolute risk accurately informally or intuitively, and the next generation of guidelines should incorporate a simple but accurate method for estimating cardiovascular risk, similar to that in the New Zealand guidelines. The decision to treat, or not treat, uncomplicated mild hypertension should be based on a formal estimate of absolute cardiovascular risk and not on an arbitrary blood pressure threshold. As regards drugs of first choice, the available evidence supports strongly the stance of JNC-V and JNC VI that diuretics and β-blockers should be preferred unless they are contraindicated, or unless there are positive indications for other drug classes.

OBJECTIVE: Methods for measuring protein binding of drugs generally require direct measurement of the concentration of unbound drug and thus may require a highly sensitive assay. In vivo ultrafiltration has been used to determine protein binding of endogenous substances. We have examined its value for measuring protein binding of drugs because it requires measurement of only the concentration of total drug, not unbound drug, in plasma. METHODS: The protein binding of aspirin and its metabolite salicylate was measured in 29 healthy subjects 20 minutes after a single oral dose of 600 mg soluble aspirin, by the new method, in vivo ultrafiltration, as well as by a standard method, in vitro ultracentrifugation. RESULTS: The data for salicylate were examined systematically to determine the optimal method of determining estimates of protein binding by in vivo ultrafiltration. Estimates of protein binding of salicylate were 81.7% +/- 10.1% (mean +/- SD) by the in vivo method and 81.6% +/- 11.3% by in vitro ultracentrifugation. Bland-Altman analysis of agreement showed that within-individual differences in percentage of protein binding determined by the two methods did not differ significantly from zero (mean difference, 0.07%; 95% confidence interval, -2.33 to +2.46). There was a highly significant correlation between estimates of protein binding by the two methods (r = 0.82; p = 0.001). Protein binding of aspirin was estimated of protein binding by the two methods (r = 0.82; p = 0.001). Protein binding of aspirin was estimated at 58.3% +/- 9.6% by in vivo ultrafiltration and could not be estimated by in vitro ultracentrifugation because the concentration of unbound aspirin in plasma was below the limit of detection for the assay. CONCLUSION: In vivo ultrafiltration can be used to measure protein binding of drugs and has potential advantages over conventional methods. A sensitive assay may not be required because the unbound drug need not be measured, measurement in vivo may maintain more physiologic conditions, and it may be useful in measuring protein binding of drugs that are degraded rapidly in vitro.

The effects of incremental infusion of angiotensin I on pressor and hormonal responses in relation to the angiotensin-converting enzyme (ACE) genotype were compared in healthy men of genotype DD (n = 8) and II (n = 8). The R(d)25 was the rate of angiotensin I infusion required to achieve a 25-mm Hg increase in diastolic pressure, and the R(s)25, that which caused a 25-mm Hg increase in systolic pressure. Changes in heart rate (HR25) were analysed at the time the R(d)25 was achieved. Serum ACE activity and plasma renin, angiotensin II, and aldosterone concentrations were measured at the start and end of the angiotensin I infusion. Serum ACE activity differed significantly between the genotypes with significantly higher mean values in DD subjects (46.3 +/- SEM 5.2 U/L) than II subjects (12.3 +/- 1.4 U/L; p0.001). Age, weight, and baseline blood pressure, heart rate, urinary sodium excretion, plasma renin, angiotensin II, and aldosterone concentrations did not differ between genotypes. The geometric mean infusion rates of angiotensin I required to achieve R(d)25 were 2.53 micrograms/min in II subjects and 2.67 micrograms/min in DD subjects (ratio of infusion rates, 0.95; 95% CI, 0.44-2.02; p0.05). The corresponding infusion rates for systolic blood pressure (R(s)25) were 4.47 micrograms/min in II subjects and 3.39 micrograms/min in DD subjects (ratio, 1.32; 95% CI, 0.49-3.55; p0.05). At the time of R(d)25, changes in heart rate from baseline were +1.2 beats/min for DD subjects and -9.5 beats/min for II subjects (diff II-DD = 10.7 beats/min; 95% CI, 6.7-14.8; p = 0.01). There were no differences in plasma renin, angiotensin, and aldosterone responses to angiotensin I infusion between the DD and II genotypes. We showed no difference in blood pressure or renin-angiotensin-aldosterone system responses to infusion of angiotensin I related to the deletion or insertion allele of the ACE gene polymorphism, but the study has insufficient power to exclude with certainty such differences. There was a significant difference between II and DD subjects in the chronotropic response to angiotensin I infusion.

1. The dermal wheal response to bradykinin is increased by drugs which inhibit angiotensin-converting enzyme, and thus provides a measure of angiotensin-converting enzyme activity at the tissue level. An insertion/deletion polymorphism of the angiotensin-converting enzyme gene predicts serum angiotensin-converting enzyme activity, but its relation to angiotensin-converting enzyme activity in tissue is unclear. 2. The relations between angiotensin-converting enzyme genotype and wheal responses to intradermal bradykinin were studied in 105 healthy subjects: 30 of genotype DD, 51 of genotype ID and 24 of genotype II. Dermal wheal area was measured by digitized planimetry and the angiotensin-converting enzyme genotype by polymerase chain reaction. 3. Bradykinin produced significant linear log dose—wheal area responses. The potency of bradykinin by parallel line bioassay did not differ significantly between the genotypes; the potency in the II subjects relative to DD subjects was 1.25 (95% confidence interval: 0.83–1.88). 4. Although the angiotensin-converting enzyme gene polymorphism is a consistent and powerful predictor of serum angiotensin-converting enzyme activity, it does not appear to predict tissue angiotensin-converting enzyme activity as measured by dermal responses to bradykinin.

1. Recent outcome trials suggest that lipid-lowering with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors is justifiable on risk-benefit grounds in subjects with serum cholesterol >5.5mmol/l who have coronary heart disease, other forms of atherosclerotic vascular disease, or who are free of vascular disease but have a risk of major coronary events ≥ 1.5% per year. Choice of an appropriate treatment policy will require (i) knowledge of the proportion of the population who will need treatment for secondary prevention, and (ii) targeting of treatment for primary prevention at a specified absolute risk of coronary heart disease events. Selection of an appropriate coronary heart disease risk for primary prevention requires consideration of the number needed to be treated to prevent one coronary heart disease event, the proportion of the population requiring treatment, the cost-effectiveness of treatment and the total cost of treatment. 2. In a random stratified sample of subjects aged 35–69 years from the Health Survey for England 1993 we first examined the prevalence of subjects with cardiovascular disease and serum cholesterol >5.5 mmol/l who may be candidates for secondary prevention. In those free of cardiovascular disease we then examined the prevalence of subjects with serum cholesterol >5.5 mmol/l who had three different levels of coronary heart disease risk: coronary heart disease event rates of 4.5% per year, 3.0% per year and 1.5% per year. These subjects may be candidates for primary prevention depending on the treatment policy selected. 3. For secondary prevention, 4.8% (95% confidence interval 4.3–5.3) of the U.K. population aged 35–69 years might be candidates for 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor treatment, comprising 2.4% (2.0 to 2.7) with a history of myocardial infarction, 1.9% (1.6 to 2.2) with angina and 0.5% (0.3–0.7) with a history of stroke-all with total cholesterol >5.5 mmol/l. The prevalence of these diagnoses with total cholesterol >5.5 mmol/l increased with age, from 1.5% at age 35–39 years to 16.2% at age 65–69 years in men, and from 0.2% at age 35–39 years to 10.0% at age 65–69 years in women. Approximately 13 people would need treatment for 5 years to prevent one coronary event, at a cost of £36 000 per event prevented. The number needing treatment for secondary prevention would increase substantially if treatment was extended to patients above 70 years of age or to those with serum cholesterol ≤ 5.5 mmol/l. 4. Primary prevention aimed at a coronary event risk of 4.5% per year would lead to treatment of only 0.3% (0.2–0.4) of those aged 35–69 years, and those treated would be predominantly older men with additional risk factors for coronary heart disease. The number needed to be treated and cost per coronary event prevented would be similar to those for secondary prevention. 5. Primary prevention targeted at subjects with a coronary event rate of 3.0% per year would entail treating 3.4% (3.0–3.9) of all those aged 35–69 years. At this level of risk, 20 people would need treatment for 5 years to prevent one coronary event, at a cost of £55 000 per event prevented. 6. Primary prevention aimed at a coronary event rate of 1.5% per year would entail treating 19.6% (18.7–20.6) of all subjects aged 35–69 years, and about 80% of men aged 60–69 years for primary or secondary prevention. At this level of risk, 40 people would need treatment for 5 years to prevent one event, at a cost of £111 000 per event saved. 7. Guidelines for 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor treatment should take into account the considerable workload and financial resources needed to implement secondary prevention of coronary heart disease, the accepted first priority. For primary prevention they need to consider the number needed to be treated to prevent one event, the number of subjects needing treatment, the cost-effectiveness of treatment and the total cost of treatment for the population. Considering only the number needed to be treated we would propose treatment for secondary prevention plus primary prevention at a coronary event rate of 3.0% per year. This would entail treating about 8.2% of the U.K. population aged 35–69 years, at an annual cost for drug therapy alone about £18 million per million of the U.K. population.

1. The effects of a single oral dose of enalapril 10 mg on serum ACE activity and blood pressure in relation to the ACE genotype were studied in 27 healthy men, n = 9 each of genotype DD, ID and II, in a parallel group study design. 2. Before treatment serum ACE activity differed significantly between the genotypes, with serum ACE activity 56% higher in DD than II subjects, and the genotype explaining 40% of between-subject variance in serum ACE activity. 3. After oral enalapril 10 mg the absolute fall in serum ACE activity was significantly larger in DD than II subjects at 2, 4, and 6 h (by 9.0 (95% CI 0.7-17.2), 10.7 (3.8-17.6), and 9.7 (2.8-16.6) nmol ml-1 min-1 respectively), but not at 24 h (fall in II > DD by 1.1 (-8.9 to 6.7) nmol ml-1 min-1). 4. Serum ACE activity remained significantly related to the ACE genotype at each time-point after enalapril, with the genotype explaining 22-46% of between-subject variance in serum ACE. 5. Falls in mean arterial pressure in response to enalapril were not significantly related to the ACE genotype, with the average fall over 6 h in DD > II genotype by 0.7 mm Hg (95% CI -5.5 to 4.1). 6. Blood pressure responses to enalapril did not correlate significantly with the initial serum ACE, or the absolute or percent reductions in serum ACE activity after enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary A 43 year old man with inoperable aortic coarctation and severe hypertension requiring near maximal anti-hypertensive treatment was admitted in severe heart failure. After 2 weeks of treatment the heart failure and blood pressure were incompletely controlled and angiotensin converting enzyme (ACE) inhibitor was started. Serum creatinine was normal before starting the ACE inhibitor and on discharge from hospital. The patient was re-admitted a week later with gross fluid retention and in renal failure. In the absence of alternative causes, a diagnosis of ACE inhibitor-induced renal failure was made and treatment was stopped. The patient required haemodialysis for 2 days and within 1 week the renal function had reverted to normal and has remained so for 1 year. We propose that the renal haemodynamics in severe aortic coarctation are similar to those in bilateral severe renal artery stenosis and advise caution in the use of ACE inhibitors for adults with aortic coarctation.

Weight reduction, moderate sodium restriction and alcohol reduction all lower blood pressure significantly in the short-term, and appear feasible in the long-term. Dynamic exercise may have a useful role in selected patients. Cessation of cigarette smoking has no important effect on blood pressure itself but is likely to improve the prognosis. No other non-pharmacological intervention warrants a place in routine management on present evidence. Regimens involving combined reduction in weight, salt and alcohol have proved less effective than drug therapy in terms of blood pressure reduction. Hypertensive patients may be shifted from just above some arbitrary intervention level to just below it by non-pharmacological treatment, and the perceived benefits of non-pharmacological management may be offset by an increased risk of vascular complications related to suboptimal blood pressure control. Moreover even simple measures such as moderate sodium restriction may affect some aspects of quality of life adversely. Non-pharmacological measures should generally be regarded as useful adjuncts to antihypertensive drug therapy rather than alternatives to it.