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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.

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: 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.

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.

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.

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.

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.

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.

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 (

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.

International audience

1. The effects of single doses of metoprolol 50 mg, metoprolol 100 mg and atenolol 100 mg on exercise tolerance were compared with placebo in a double-blind random cross-over study in 12 healthy subjects. Nine subjects were extensive metabolisers of debrisoquine, and three were poor metabolisers. 2. Three hours after dosing beta-adrenoceptor blocker treatments significantly reduced exercise heart rate, prolonged time to complete exercise, and increased subjective fatigue measured by visual analogue scale. 3. Scores for subjective fatigue did not correlate with reduction in exercise heart rate or prolongation of exercise time. Exercise time prolongation was weakly but not significantly correlated with exercise heart rate reduction. 4. When compared with placebo, prolongation of exercise time and increased fatigue with metoprolol were not significantly related to debrisoquine oxidation phenotype or to the debrisoquine/4-hydroxydebrisoquine (D/4OH-D) ratio. 5. When metoprolol responses were compared with those for atenolol, changes in exercise time and fatigue scores were significantly related to oxidation phenotype. For metoprolol 100 mg, poor metabolisers required 20.8 s longer to complete exercise (P less than 0.05) and had higher fatigue scores by 78% (P less than 0.05) as compared with extensive metabolisers.(ABSTRACT TRUNCATED AT 400 WORDS)

1. The effects of 4-6 weeks treatment with placebo, potassium chloride 32 mmol 12 hourly, and spironolactone 25 mg 12 hourly upon the plasma potassium concentration-time profile were examined in hypertensive patients taking bendrofluazide 5 mg daily. 2. When compared with placebo, potassium chloride increased peak plasma potassium concentration (P less than 0.05), 12 h AUC for plasma potassium (P less than 0.1), and 12 h urine potassium excretion (P = 0.002). Spironolactone increased peak plasma potassium concentration (P less than 0.05), and 12 h AUC for plasma potassium (P less than 0.05), compared with placebo values. 3. Potassium chloride and spironolactone did not differ significantly in any respect other than 12 h urine potassium excretion. The 12 h AUC for plasma potassium was 35% larger with spironolactone than potassium chloride (not significant). 4. With both active drugs peak plasma potassium was observed 2-3 h after dosing, and efficacy tended to wane towards 12 h. However, variability of plasma potassium within the dose interval was not increased markedly, and 12 hourly dosing is probably satisfactory for both potassium chloride and spironolactone at the doses studied.

The effects of a single dose of sulindac 200 mg and placebo on the capsaicin-induced cough reflex were studied in a two-phase double-blind crossover study in 18 healthy subjects. Sulindac increased the threshold for capsaicin cough response significantly, but did not alter D5, peak response, or the total cough response when compared with placebo values.

SIR—We regret that there was an important error in the Sheffield table (Aug 10, p 387), and a corrected version is presented on p 1252. The error in the original was in the table for men only, and arose because the column headings indicating different combinations of risk factors were accidentally transposed as the final table was prepared. Thus the numbers in the table are correct, but do not always correspond to the risk factor combinations shown above them. We are aware that some colleagues have used the table to evaluate individuals, and will want to know what the practical consequences may be. The inaccurate table still predicts, on average, a coronary heart disease (CHD) event rate of 3·0% per year. For eight of the twelve columns in the table for men the risk targeted was acceptably accurate, ranging from 2·8 to 3·2% CHD events per year. Two of the columns would target treatment at men with a lower CHD risk—1·9% and 2·3% per year, respectively. Statin treatment is readily justifiable at this level of risk and this inaccuracy should therefore cause no harm. However, in two columns men were signalled as not needing treatment when their risk of CHD was in fact substantially higher than 3·0% per year—at 3·8% and 4·2% per year. These men should be reassessed by the corrected Sheffield table reproduced overleaf. They can in fact be identified readily, because they are all men with hypertension and left ventricular hypertrophy (LVH) shown by electrocardiography. We therefore suggest that any man with hypertension plus LVH who was assessed by the Sheffield table and not treated should be reassessed with the corrected table. We apologise to colleagues for any inconvenience caused by our error.

EDITOR,--The OXCHECK study showed significant reductions in total cholesterol concentration (3.1%) and blood pressure (2.5/1.5 mm Hg) with health checks over three years.1 The reductions in cholesterol concentration are in line with responses shown in previous controlled trials.2 The authors seem in some doubt about whether these effects are large enough to justify the cost of the health checks. This may be clearer when the projected …

The incidence and prevalence of cough related to enalapril was assessed by spontaneous reporting and a visual analogue scale during a 6 month random double-blind parallel-group study comparing enalapril with nifedipine. Cough was reported spontaneously by 6.2% of enalapril-treated patients, and by none on nifedipine (NS). No patient had to discontinue enalapril because of cough. After 24 weeks treatment increases in visual analogue scale scores for cough frequency greater than or equal to 8 mm were more common for enalapril than nifedipine (difference 21.5%, 95% CI 7.3-35.7%). Increased cough frequency by visual analogue scale was present throughout the study in women, but less consistently in men. High scores for cough were not related to the dose of enalapril. Cough with enalapril was not an important problem during the 6 months of treatment. However increased cough frequency could be detected by visual analogue scale, with a frequency consistent with that observed in open clinic-based studies of longer duration. These findings suggest that ACE inhibitor-induced cough may increase in severity over time, and that even a period of 6 months treatment is too short to evaluate this side-effect adequately.