Wilfred W. Yeo

Coronary and cardiovascular risk estimation for primary prevention: validation of a new Sheffield table in the 1995 Scottish health survey population.

Abstract Objective: 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. Design: 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 ≥years; aspirin treatment when the risk is ≥ 15% over 10 years; and the treatment of mild hypertension when the cardiovascular risk is≥0% over 10 years. Setting: The table is designed for use in general practice. Subjects: Random sample of 1000 people aged 35–64 years from the 1995 Scottish health survey. Main outcome measures: Sensitivity, specificity, and positive and negative predictive values of the table. Results: 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 for <50% with a coronary risk of <5% 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. Conclusion: 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.

Sheffield risk and treatment table for cholesterol lowering for primary prevention of coronary heart disease

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 or 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.

Prostaglandin E2 activates EP2 receptors to inhibit human lung mast cell degranulation

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.

Association of panic disorder and panic attacks with hypertension

PURPOSE Previous studies of the association between hypertension and panic disorder were uncontrolled or involved small numbers of patients. PATIENTS AND METHODS 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. RESULTS The prevalence of current (previous 6 months) panic attacks was significantly greater in primary care patients with hypertension (17%, P <0.05) and hospital-based hypertensive patients (19%, P <0.01) than in normotensive patients (11%). Similar results were seen for lifetime panic attacks (35% versus 39% versus 22%; both P for comparisons with normotensive patients <0.001). The prevalence of panic disorder was significantly greater in primary care patients with hypertension (13%) than normotensive patients (8%, P <0.05). 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 (P <0.01). CONCLUSIONS Physicians caring for patients with hypertension should be aware of the significantly greater prevalence of panic attacks in these patients.

Panic disorder, anxiety and depression in resistant hypertension : a case-control study

Background It has been suggested that panic disorder can cause or contribute to hypertension or resistance to antihypertensive drugs. Objective To compare the prevalences of panic disorder, panic attacks, anxiety and depression between patients with resistant hypertension and age- and sex-matched patients with non-resistant hypertension. Design A case–control study of patients attending the Sheffield Hypertension Clinic, using self-completed postal questionnaires to assess panic disorder, anxiety and depression. Patients Cases with resistant hypertension were defined as patients who presently or previously had systolic blood pressure above 160 mmHg or diastolic blood pressure above 90 mmHg despite the use of three or more antihypertensive agents at full dose. For each of 136 cases, one control with non-resistant hypertension, defined as controlled to ≤ 160/90 mmHg by one or two antihypertensive agents, was identified by a bias-free method. Cases and controls were matched for age and sex. Main outcome measures Lifetime and current prevalence of panic attacks, the prevalences of panic disorder, anxiety and depression by Hospital Anxiety and Depression Scale scores, and the severity and frequency of panic attacks. Results Of the resistant hypertensive patients, 33% had experienced a panic attack compared with 39% of the control non-resistant hypertensives (resistant – non-resistant −6%, 95% confidence interval −19 to +7%). Twelve per cent of the resistant patients and 14% of controls fulfilled the criteria for a current or previous diagnosis of panic disorder (resistant – non-resistant −2%, 95% confidence interval −11 to +7%). There were also no significant differences between the groups in the prevalences of current panic attacks, panic attacks rated as moderate or worse, spontaneous panic attacks and in the frequency of panic attacks. There remained no significant difference between the groups for panic attacks and panic disorder when the analysis was limited to those patients who had idiopathic hypertension. The two groups did not differ significantly in scores for anxiety and depression measured by the Hospital Anxiety and Depression Scale. Conclusion We observed no differences in the prevalences of panic, anxiety and depression between patients with resistant hypertension and non-resistant controls. These factors are probably not implicated in resistance to drug treatment. However, the prevalences of panic disorder and panic attacks were remarkably high in both groups of patients attending a hospital hypertension clinic. The relationship between panic disorder and hypertension deserves further study in a general hypertensive population.

The rationale for differing National recommendations for the treatment of hypertension

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 beta-blockers should be preferred unless they are contraindicated, or unless there are positive indications for other drug classes.

The Sheffield table for primary prevention of coronary heart disease: corrected

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.

Pressor and hormonal responses to angiotensin I infusion in healthy subjects of different angiotensin-converting enzyme genotypes.

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; p < 0.001). 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; p > 0.05). 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; p > 0.05). 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.

Double-blind comparison of losartan, lisinopril and hydrochlorothiazide in hypertensive patients with a previous angiotensin converting enzyme inhibitor-associated cough

Objective: To compare the incidence of cough with the angiotensin II antagonist losartan, the angiotensin converting enzyme inhibitor lisinopril, and hydrochlorothiazide in hypertensive patients with previous angiotensin converting enzyme inhibitor cough Design: Double-blind random stratified parallel-group comparison of losartan 50 mg, lisinopril 20 mg and hydrochlorothiazide 25 mg, each given once daily for a maximum of 8 weeks. Cough detected by self-administered questionnaire (the primary end-point) and cough frequency by visual analogue scale (a secondary end-point) Setting: Hypertension clinics in 20 centres in 11 countries Patients: 135 hypertensive patients, all non-smokers, with angiotensin converting enzyme inhibitor cough confirmed by lisinopril rechallenge then placebo dechallenge Results: Incidence of cough with losartan (29%) lower than that for lisinopril (72%; P<0.01) and similar to that for hydrochlorothiazide (34%). Cough frequency by visual analogue scale lower for losartan than lisinopril (P<0.01) and similar to that for hydrochlorothiazide Conclusions: The specific selective angiotensin II receptor (AT1) antagonist losartan does not cause cough in patients with previous angiotensin converting enzyme inhibitor cough. Angiotensin converting enzyme inhibitor cough is likely to be related to kininase II inhibiting action

Metabolic effects of diuretics.

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.