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OBJECTIVE—To determine the proportion of the population, firstly, with cholesterol ⩾ 5.0 mmol/l and, secondly, with any cholesterol concentration, who might benefit from statin treatment for the following: secondary prevention of coronary heart disease (CHD); primary prevention at CHD risk 30%, 20%, 15%, and 6% over 10 years; and primary prevention at projected CHD risk 20% over 10 years (CHD risk at age 60 years if actual age

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.

Intermittent claudication is a common condition of the elderly, occurring in 3 to 20% of individuals over the age of 65 years. Although local disease is usually benign, life expectancy in patients with intermittent claudication is reduced by approximately 10 years due to associated cardiovascular mortality. Several classes of drugs have been used in intermittent claudication, but clinical studies evaluating their efficacy leave much to be desired. Pentoxifylline (oxpentifylline), a rheological agent, and naftidrofuryl, an enhancer of aerobic metabolism, are the 2 most widely investigated and utilised drugs. The combined results of 10 placebo-controlled studies with pentoxifylline and 4 with naftidrofuryl estimate increases in claudication distances of 51 and 42%, respectively. How-† The views expressed in this article are those of the authors and should not be taken to represent the official view of the UK Medicines Control Agency. ever, due to publication bias, these figures are probably overestimates of the true benefit from treatment with these drugs. It is likely that any benefit from pentoxifylline or naftidrofuryl is small and of little clinical importance. The suggestion that naftidrofuryl has greater efficacy in older patients remains unproven. Other classes of drugs including vasodilators, antiplatelet drugs, anticoagulants and prostaglandins have not been shown to be effective. Only 2 approaches to the management of intermittent claudication have been shown convincingly to be of benefit: stopping smoking and exercising regularly.

Increasingly HMG CoA reductase inhibitors (statins) are being used for primary prevention of vascular disease in patients with a raised cholesterol but at low absolute risk of coronary heart disease (CHD). This study uses clinical trial results to explore the limits of absolute safety for statin use in such patients.The major placebo controlled statin outcome trials were identified by automated and manual literature searches. Principal results including all cause mortality in placebo and intervention groups and baseline values of standard coronary risk factors were abstracted for each trial. For the trials identified the reduction in overall mortality with statin treatment for each study was regressed against the underlying CHD risk of the population recruited into that trial using a statistically robust method.The regression line describing the relationship between mortality benefit and risk suggests that statin use could be associated with an increase in mortality of 1% in 10 years. This would be sufficiently large to negate statin's beneficial effect on CHD mortality in patients with a CHD event risk less than 13% over 10 years.Absolute safety of statins has not been demonstrated for patients at low risk of CHD. Patients absolute risk of CHD should be calculated before starting statin treatment for primary prevention. Extensions of such treatment to low risk patients should await further evidence of safety.

This article summarises the new British Hypertension Society guidelines for management of hypertension, which have been published in full.1 Since the previous guidelines 2 3 much new evidence has emerged on optimal blood pressure targets4; management of hypertension in diabetic patients4–7; treatment of isolated systolic hypertension8; comparison of the antihypertensive efficacy and tolerability of different drug classes9–11; the role of non-pharmacological measures for prevention 12 13 and treatment of hypertension14; and additional benefits associated with the use of aspirin and statins. Of concern is that national surveys continue to reveal incomplete detection, treatment, and control of hypertension.15 Furthermore, treated hypertensive patients still die prematurely from cardiovascular disease.16 These guidelines aim to present the best currently available evidence on hypertension management and their implementation. #### Summary points Use non-pharmacological measures in all hypertensive and borderline hypertensive people Initiate antihypertensive drug treatment in people with sustained systolic blood pressure ≥160 mm Hg or sustained diastolic blood pressure ≥100 mm Hg Decide on treatment in people with sustained systolic blood pressure between 140 and 159 mm Hg or sustained diastolic blood pressure between 90 and 99 mm Hg according to the presence or absence of target organ damage, cardiovascular disease, diabetes, or a 10 year coronary heart disease risk ≥15% according to the Joint British Societies coronary heart disease risk assessment programme or risk chart Optimal blood pressure treatment targets are systolic blood pressure

To review the findings of prospective controlled trials of antihypertensive treatment and determine whether the evidence they have provided is embodied satisfactorily in current national and international guidelines for hypertension management.Conventional guidelines all advise prompt treatment of moderate-to-severe hypertension and treatment of even mild hypertension in subjects with cardiovascular disease, target organ damage or diabetes, and in the elderly; and treatment of isolated systolic hypertension in the elderly. All acknowledge that evidence for efficacy and safety of treatment is strongest for thiazide diuretics and beta-blockers.Conventional guidelines all emphasize the importance of long-term blood pressure, measured over some months, for treatment decisions. However the blood pressure for routine treatment varies from 160/100 mmHg (British Hypertension Society) to 140/90 mmHg (Joint National Committee V). This dictates very large differences in the number of patients to be treated to prevent a cardiovascular disease event and in the proportion of the population to be treated, yet the reasons for these differences are not explicit. None of the conventional guidelines is entirely satisfactory. The more conservative British Hypertension Society policy may leave untreated some middle-aged men who ought to be treated. The more aggressive Joint National Committee V policy will lead to treatment of some young subjects who have only a remote chance of benefit, at very high cost, and possibly with adverse harm-benefit consequences. RISK-BASED GUIDELINES: Guidelines developed in New Zealand target absolute cardiovascular disease risk in mild hypertension and have the potential to correct this shortcoming of conventional guidelines. However they require further consideration as regards the number needed to treat which is acceptable to well-informed patients, the appropriate estimate of relative cardiovascular disease risk reduction by treatment in mild hypertension, the pattern of treatment which will emerge and their acceptability in ordinary practice.Comparative evaluation will be needed to determine whether the outcome is better with conventional guidelines, which are simple but at the expense of accuracy, or with risk-targeted guidelines, which are more accurate but at the expense of simplicity.

Seit der Erstbeschreibung eines durch ACE-Hemmer-Behandlung verursachten Hustens ist unsere Kenntnis uber die klinischen Charakteristika, die Inzidenz und Pravalenz dieser lastigen Nebenwirkung erheblich gewachsen. Zahlreiche Studien haben bestatigt, das ein persistierender trockener Husten die haufigste subjektive Nebenwirkung wahrend einer langfristigen Behandlung mit ACE-Inhibitoren und der haufigste Grund fur eine Beendigung der Therapie ist. Jedoch sind andere Aspekte des ACE-Inhibitor-Hustens nach wie vor unklar. Wir kennen nicht die Pathogenese des Hustens und wissen auch nicht, warum einige Patienten diese Nebenwirkung entwickeln, andere jedoch nicht. Eine kurzlich publizierte Untersuchung mit dem spezifischen Angiotensin-II-Rezeptor-Antagonisten Losartan bei Patienten, die ACE-Hemmer-Husten hatten, erbrachte wertvolle Einblicke in die naturliche Entstehungsgeschichte und die Mechanismen des Hustens [18]. In dieser Arbeit geben wir einen Uberblick uber den gegenwartigen Wissensstand zum ACE-Hemmer-Husten und uber neue Erkenntnisse, die wir aus der Studie mit Losartan erhalten haben.

1. In eight hypertensive patients with ACE inhibitor-induced cough the resolution of the cough was examined in a prospective observational study over 4 weeks duration. Resolution of cough was measured by visual analogue scales and questionnaire at baseline and days 3, 7, 14 and 28. In addition changes in cough sensitivity to inhaled capsaicin, and skin responses to bradykinin and substance-P were measured at the same time points. 2. All patients recorded significant subjective improvement in cough questionnaire scores for severity and night time waking, and by visual analogue scales for severity and frequency of cough (all P < 0.0005 for trend from day 0-28). Significant changes in subjective measures were recorded by 3 to 7 days for most measures, but further reductions were observed up to day 28 (all P < 0.01 day 28 vs day 0). 3. The sensitivity to inhaled capsaicin fell over the 28 days of study after stopping enalapril. The potency of capsaicin relative to day 0 was reduced to 0.25 (95% CI 0.07-0.87) by day 14, and to 0.20 (95% CI 0.06-0.67) by 28 days. 4. After stopping enalapril there was a highly significant reduction in wheal area produced by intradermal bradykinin, with the majority of the effect seen by day 3 (P < 0.0005). The wheal area to intradermal substance-P also declined with time after stopping enalapril, but significant changes were not observed until 14 days (P < 0.01). 5. Multiple regression analysis of the rates of decline for the subjective and objective measures of cough showed significant associations between the response to inhaled capsaicin and the VAS scores for severity of cough (P = 0.005) and frequency of cough (P = 0.011). Capsaicin response was not related significantly to the severity of cough measured by self-administered questionnaire. 6. There was a significant association between bradykinin response and VAS scores for frequency of cough (P < 0.04) and severity of cough (P < 0.05), but not with cough by questionnaire or the capsaicin response. The response to substance-P did not relate significantly to any of the measures of cough. 7. Cough caused by enalapril improved markedly by 14 days but took up to 28 days to resolve. It was associated with increased sensitivity to inhaled capsaicin which decreased over 28 days, and which paralleled changes in subjective cough scores.

One hundred and thirty five non-smoking hypertensive patients with ACE inhibitor cough confirmed by lisinopril rechallenge and placebo dechallenge were recruited into a double-blind random parallel-group comparison of losartan 50 mg, lisinopril 20 mg and hydrochlorothiazide 25 mg each given once daily for a maximum of 8 weeks. The aim of the study was to compare the incidence of cough with the angiotensin II antagonist losartan, the ACE inhibitor lisinopril and the hydrochlorothiazide in hypertensive patients with previous ACE inhibitor cough. Cough detected by self-administered questionnaire was the primary end-point, and cough frequency by visual analogue scale a secondary end-point. The incidence of cough with losartan (29%) was lower than that for lisinopril (72%, P0.01) and similar to that for hydrochlorothiazide (34%). Cough frequency by visual analogue scale was lower for losartan than lisinopril (P0.01) and similar to that for hydrochlorothiazide. The specific selective AT1 angiotensin II receptor antagonist losartan is significantly less likely than lisinopril to cause cough in patients who previously have had ACE inhibitor cough. ACE inhibitor cough is likely to be related to non-specific kininase II inhibition.

Weight reduction, moderate salt restriction and alcohol reduction are effective in lowering blood pressure (BP), and are feasible interventions for long-term management of hypertension. When used in combination these non-pharmacological measures are significantly inferior to drug therapy in anti-hypertensive effect. When they are implemented as a first step in the treatment of mild hypertension, resorting to drug therapy only if non-pharmacological measures fail, anti-hypertensive drugs can be avoided in about 40% of patients. However, BP control is again significantly inferior with this strategy compared with drug therapy without non-pharmacological advice. Those given advice on non-pharmacological measures may therefore have suboptimal protection against cardiovascular complications. This is particularly so when the threshold for drug treatment is set at a DBP ofor = 100 mmHg, as many patients will be left untreated with DBPs between 90 and 99 mm Hg as a result of non-pharmacological measures. Non-pharmacological treatment may thus stand between patients and anti-hypertensive drug therapy, which nowadays is simple, well-tolerated, safe and proven effective in preventing cardiovascular disease. The role of non-pharmacological therapy needs to be reconsidered.

Guidelines for the management of hypertension, and those for hyperlipidaemia, advocate measurement of cholesterol in all hypertensive subjects. It is suggested that knowledge of serum cholesterol should influence the choice of anti-hypertensive agent because thiazides and beta-blockers may influence lipids adversely. However, the changes in lipids associated with low-dose thiazides and beta-blockers are small, not sustained and do not appear to affect prognosis adversely. Some believe that knowledge of serum cholesterol may help target the treatment of mild hypertension more accurately by predicting an increased risk of vascular complications of hypertension. However, serum cholesterol does not predict the risk of cardiovascular complications in hypertensive women. It does predict coronary heart disease (but not stroke) in men, but coronary risk can be estimated satisfactorily without knowledge of serum cholesterol. Suggestions that cholesterol should be lowered in hypercholesterolaemic hypertensive patients to reduce the incidence of coronary heart disease are understandable. However, the diet recommended for this has no useful effect on serum cholesterol, and the benefit of lipid-lowering drugs for cholesterol reduction only exceeds the risk in patients at very high risk of coronary mortality, for example those who have had a myocardial infarction. Hypertension alone will not place individuals at high enough risk to warrant drug therapy for cholesterol reduction. We conclude that the current guidelines are incorrect, and that routine measurement of cholesterol in all hypertensive patients is not justified.

There is a strong association between cigarette smoking and accelerated hypertension. In mild hypertension smoking cigarettes has a distinct pressor effect and caffeine a small but more prolonged pressor action. Coffee and cigarette smoking together have an additive effect on blood pressure (BP). We have examined the interaction of cigarette smoking and drinking coffee on the BP of six patients who presented with accelerated hypertension (mean BP 240/140 mm Hg) and were heavy smokers and caffeine users. After initial control of the BP, the effects of smoking alone, coffee plus smoking, and placebo were examined in a balanced cross-over study. Baseline BP averaged 154/91 mm Hg and remained stable for 90 min after abstention from smoking and caffeine (placebo). Cigarette smoking without caffeine caused a modest rise in BP (mean 9/8 mm Hg), but the combination of coffee plus cigarette smoking caused a progressive increase in BP to an average 21/17 mm Hg (P0.05/P0.002) higher than placebo values. The effect of coffee was significantly additive to that of smoking alone. Smoking plus coffee ingestion shifted the BP from acceptable (155/94 mm Hg) to poor control (175/107 mm Hg). This pressor effect was observed despite treatment, and with amounts of caffeine and cigarettes which were in no way unusual for these patients. We propose that the association of cigarette smoking with accelerated hypertension may reflect an extreme pressor effect of combined smoking and caffeine use in some patients.

Hyperventilation is an important feature of panic disorder, and an association has been reported between panic disorder and hypertension. We have examined the effect of hyperventilation on the blood pressure (BP) of healthy subjects. Twenty six subjects were randomised in a balanced two-period cross-over study to compare the effects of hyperventilation with that of normal breathing on sitting BP, heart rate and the electrocardiogram. Each study phase lasted 40 min, with 15 min of baseline observation, 5 min of hyperventilation or normal breathing, and 20 min of continued observation. Hyperventilation significantly increased SBP by 8.9 mm Hg (95% CI 3.8-13.8, P0.01), diastolic blood pressure by 8.2 mm Hg (95% CI 1.7-14.7, P0.05), mean arterial pressure by 10.0 mm Hg (95% CI 3.3-16.7, P0.01) and heart rate by 36 beats/min (95% CI 31-44, P0.01). The changes in diastolic and mean arterial pressure correlated significantly with the total volume of air expired during hyperventilation (r = 0.57, p0.01 and r = 0.50 P0.01, respectively), but not with the change in expired carbon dioxide. In the electrocardiogram, T wave changes occurred in the inferior leads in 10 of 26 subjects, but there were no significant changes in other measurements. Hyperventilation significantly increased the BP of healthy subjects, and the role of hyperventilation in the link between panic disorder and hypertension deserves further study.

To compare the incidence of cough in patients with a history of angiotensin converting enzyme (ACE) inhibitor-related cough who received losartan [a type 1 angiotensin II (Ang II) receptor antagonist], lisinopril (an ACE inhibitor) or hydrochlorothiazide (a diuretic).An international, multicentre, randomized double-blind, parallel-group controlled trial.Outpatient clinics at 20 tertiary care medical centres in 11 countries.One hundred and thirty-five patients with uncomplicated primary hypertension with a history of ACE inhibitor-related cough were randomly assigned to the double-blind treatment phase and completed the study.After confirming that the cough was ACE inhibitor-related by a single-blind rechallenge, followed by a placebo washout period, patients were randomly assigned to receive 50mg losartan, 20mg lisinopril or 25mg hydrochlorothiazide once a day for 8 weeks.Cough incidence, severity and frequency were assessed by a self-administered questionnaire and a visual analogue scale.The percentage of patients who complained of cough was significantly higher with lisinopril than with losartan or hydrochlorothiazide. The mean visual analogue scale scores for patients treated with lisinopril demonstrated that these patients coughed more frequently than those who received losartan or hydrochlorothiazide.The incidence of cough related to the type 1 Ang II receptor antagonist losartan is significantly lower than that observed with lisinopril, and similar to that observed with hydrochlorothiazide in patients with a rechallenged ACE inhibitor cough. Type 1 Ang II receptor antagonists represent a potential new treatment for hypertensive patients in whom ACE inhibitors are indicated, but who develop a cough with these agents.

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.

OBJECTIVE--To audit avoidable deaths from stroke and hypertensive disease. DESIGN--Details of care before death were obtained from general practitioners and other doctors, anonymised, and assessed by two experts against agreed minimum standards of good practice for detecting and managing hypertension. SETTING--Health authority with population of 250,000. SUBJECTS--All patients under 75 years who died of stroke, hypertensive disease, or hypertension related causes during November 1990 to October 1991. MAIN OUTCOME MEASURES--Presence of important avoidable factors and departures from minimum standards of good practice. RESULTS--Adequate information was obtained for 88% (123/139) of eligible cases. Agreement between the assessors was mostly satisfactory. 29% (36/123, 95% confidence interval 21% to 37%) of all cases and 44% (36/81, 34% to 55%) of those with definite hypertension had avoidable factors that may have contributed to death. These were most commonly failures of follow up and continuing smoking. Assessment against standards of minimum good practice showed that care was inadequate but not necessarily deemed to have contributed to death, in a large proportion of patients with definite hypertension. Common shortcomings were inadequate follow up, clinical investigation, and recording of smoking and other relevant risk behaviours. CONCLUSIONS--This method of audit can identify shortcomings in care of patients dying of hypertension related disease.

To compare low-dose thiazides to beta-blockers, angiotensin converting enzyme (ACE) inhibitors, calcium antagonists and alpha-blockers for simplicity, tolerability, efficacy, safety and cost-effectiveness as first-line treatment for hypertension.Review of short-term comparative studies, and the outcome of long-term trials with vascular complications of hypertension as endpoints. SIMPLICITY: Among the advantages of thiazides are a flat dose-response; no dose titration; effectiveness when used once a day; no first-dose hypotension; and few contra-indications.Thiazides are the best tolerated agents in patients over the age of 60 years and in younger women. They sometimes cause gout and impotence in younger men, in whom beta-blockers are equally acceptable first-line therapy.Thiazide-based regimens have consistently reduced vascular complications of hypertension, the real measure of efficacy. There is little evidence that regimens based on other drugs are effective in this sense.Concerns that thiazide-induced biochemical changes cause coronary events are baseless. An overview of outcome trials shows that thiazide-based treatment reduces coronary events significantly, and the reduction is not significantly different from that predicted by epidemiological data. Thiazide-based therapy has also reduced coronary events significantly and substantially in elderly patients with isolated systolic hypertension.Low-dose thiazide treatment needs minimal monitoring, and has proved most cost-effective in formal analyses.Low-dose thiazide treatment is a clear first-line choice for patients aged over 60 years and younger women, except those with diabetes or gout. In younger men there is little to choose between thiazides and beta-blockers.

Epidemiological studies have shown that a significant proportion of the population have diastolic blood pressures above 100 mmHg even on rechecking. Trials from many countries demonstrate that treatment of such patients with hypotensive drugs reduces the risk of stroke, heart failure and renal failure.1,2,3,4 The benefit in terms of a reduced risk of myocardial infarction is smaller but an overview of the trials shows that even this disorder may be reduced by about 14%.5 Thus, the detection and treatment of people with high blood pressure represents one of the major challenges in the prevention of cardiovascular disease. Reduction in blood pressure may be achieved by means other than drug treatment such as weight loss, restricting excess alcohol intake and cutting back on salt consumption. Further benefit may be gained by getting patients to quit smoking thus preventing added cardiovascular damage. In normal practice pharmacological treatment would only be initiated if the blood pressure remains elevated despite such measures.

Treatment with thiazide diuretics causes impaired glucose tolerance, biochemical diabetes, and insulin resistance. The effect of diuretics on glucose tolerance is clearly dose-related. Spironolactone does not impair glucose tolerance, even at high dosage, but differences among other diuretics could be due to comparisons at doses that are not equal. Diuretic-induced changes in glucose metabolism are not conclusively related to altered potassium homeostasis, and impaired glucose tolerance occurs even when relatively low doses of thiazide are combined with potassium-sparing agents. The effects of diuretics on glucose homeostasis are in large part and probably entirely reversible. These disturbances of glucose metabolism have been detected only by detailed biochemical testing, and their clinical relevance is uncertain. In established diabetes, diuretics have a rapid and substantial adverse effect on metabolic control. In nondiabetic subjects, diuretics rarely cause or trigger a serious hyperosmolar nonketotic diabetic syndrome. Otherwise, it is not known whether the metabolic changes cause clinical diabetes or lead to microvascular complications in the long term. Evidence from large outcome trials suggests that biochemical diabetes, glucose intolerance, and insulin resistance do not increase the risk of coronary heart disease in treated hypertensive patients. Diuretics should be avoided in patients with diabetes unless their use is essential. Otherwise, a low dose of thiazide remains as excellent choice for first-line antihypertensive therapy. Dihydropyridine calcium antagonists, diltiazem, and verapamil appear to have no important effects on glucose homeostasis. There is very limited evidence that selective alpha-antagonists increase insulin sensitivity. The importance of metabolic differences between drug classes will be established only by comparative outcome trials with coronary events as the end point.

OBJECTIVE--To determine the effects of the beta 1 selective adrenoceptor blocker atenolol, the dihydropyridine calcium antagonist nifedipine, and the combination of atenolol plus nifedipine on objective and subjective measures of walking performance and foot temperature in patients with intermittent claudication. DESIGN--Randomised controlled double blind four way crossover trial. SETTING--Royal Hallamshire Hospital, Sheffield. SUBJECTS--49 patients (40 men) aged 39-70 with chronic stable intermittent claudication. INTERVENTIONS--Atenolol 50 mg twice daily; slow release nifedipine 20 mg twice daily; atenolol 50 mg plus slow release nifedipine 20 mg twice daily; placebo. Each treatment was given for four weeks with no washout interval between treatments. MAIN OUTCOME MEASURES--Claudication and walking distances on treadmill; skin temperature of feet as measured by thermistor and probe; blood pressure before and after exercise; subjective assessments of walking difficulty and foot coldness with visual analogue scales. RESULTS--Atenolol did not significantly alter claudication distance (mean change -6%; 95% confidence interval 1% to -13%), walking distance (-2%; 4% to -8%), or foot temperature. Nifedipine did not alter claudication distance (-4%; 3% to -11%), walking distance (-4%; 3% to -10%), or foot temperature. Atenolol plus nifedipine did not alter claudication distance but significantly reduced walking distance (-9%; -3% to -15% (p less than 0.003)) and skin temperature of the more affected foot (-1.1 degrees C; 0 to -2.2 degrees C (p = 0.05)). These effects on walking distance and foot temperature seemed unrelated to blood pressure changes. CONCLUSIONS--There was no evidence of adverse or beneficial effects of atenolol or nifedipine, when given singly, on peripheral vascular disease. The combined treatment, however, affected walking ability and foot temperature adversely. This may have been due to beta blockade plus reduced vascular resistance, which might also explain the reported adverse effects of pindolol and labetalol on claudication.

The prevalence and severity of cough during long-term enalapril treatment were examined by comparing a cohort of 136 hypertensive patients who started treatment with enalapril with consecutive age and sex-matched patients who commenced nifedipine therapy during the same period. Cough and other symptoms were assessed by a questionnaire designed to avoid bias towards reporting cough. After a mean of 27 months' treatment patients on enalapril had an excess of persistent cough (16 per cent, 95 per cent CI 7-25, p less than 0.01), voice change (14 per cent, 95 per cent CI 2-27, p less than 0.05) and sore throat (10 per cent, 95 per cent CI -0.1 to 20.3 per cent, p less than 0.01) when compared to nifedipine-treated patients. The cough was usually dry, moderate or severe, paroxysmal, and troublesome at night. Cough tended to be more common in women (23 per cent vs. 7.2 per cent), non-smokers, and at higher doses of enalapril, but was not related to age, duration of treatment, or chronic respiratory disease. Dry cough commonly persists as a troublesome side-effect during long-term enalapril treatment, and is often associated with voice change and sore throat.

The prevalence and severity of cough during long-term enalapril treatment were examined by comparing a cohort of 136 hypertensive patients who started treatment with enalapril with consecutive age and sex-matched patients who commenced nifedipine therapy during the same period. Cough and other symptoms were assessed by a questionnaire designed to avoid bias towards reporting cough. After a mean of 27 months' treatment patients on enalapril had an excess of persistent cough (16 per cent, 95 per cent CI 7-25, p less than 0.01), voice change (14 per cent, 95 per cent CI 2-27, p less than 0.05) and sore throat (10 per cent, 95 per cent CI -0.1 to 20.3 per cent, p less than 0.01) when compared to nifedipine-treated patients. The cough was usually dry, moderate or severe, paroxysmal, and troublesome at night. Cough tended to be more common in women (23 per cent vs. 7.2 per cent), non-smokers, and at higher doses of enalapril, but was not related to age, duration of treatment, or chronic respiratory disease. Dry cough commonly persists as a troublesome side-effect during long-term enalapril treatment, and is often associated with voice change and sore throat.

Drug treatment of hypertension reduced the incidence of stroke by 40% and prevented cardiac and renal failure, but had less effect on coronary artery disease in the major trials. Coronary events were reduced by about 14% (confidence limits of 4-22%), which compares to the reduction of 20-25% anticipated from epidemiological studies. Any shortfall in coronary prevention that could be attributable to adverse effects of antihypertensive drugs would therefore amount to only 6-11% of all coronary events, and could easily arise by chance. At present, there are no grounds for preferring one class of drug over another from the point of view of coronary prevention, or for altering the "target" diastolic pressure during treatment. Strategies other than blood pressure reduction aimed at preventing coronary disease in hypertensive subjects need to be explored. They should, however, be examined in large controlled outcome trials, and should not be introduced to ordinary practice on the basis of the inadequate evidence currently available.

In a cohort of 136 hypertensive patients started consecutively on enalapril the incidence of persistent dry cough by life-table analysis was 14.6% (95% CI 10.2-19.0%). The incidence in women (19.2%; 95% CI 11.3-27.1%) was twice that in men (9.7%; 95% CI 6.6-12.8%). Dry cough was unrelated to age, smoking habit, renal function, or the dose and duration of enalapril treatment. In one half of patients who developed cough enalapril had to be stopped. The incidence of withdrawal due to cough was 6.0% (95% CI 4.5-7.5%), and cough was by far the most common reason for discontinuing enalapril treatment. Reviewing previous studies of enalapril-induced cough, it is evident that postmarketing surveillance studies have grossly underestimated the incidence and importance of this side-effect. Surveys in hospital clinics have slightly underestimated the true incidence through failure to use life-table methods of analysis.

ACE inhibitors have antihypertensive efficacy similar to that of thiazides, beta-blockers and calcium antagonists. They are simple to prescribe and to take, and are relatively free from subjective side-effects apart from persistent dry cough. There are few specific concerns about safety, but experience of long-term use is still relatively limited. They are valuable additional or alternative antihypertensive drugs when standard therapy is contraindicated or fails to control blood pressure.

EDITOR, - It is ironic that Douglas G Altman's editorial castigating poor medical research1 should appear one week after the paper by Angela A Rivellese and colleagues, which concluded that two test diets “are suitable for treatment of hypercholesterolaemia.” 2 There are many problems with this study. The study is indeed controlled in the sense that its design permitted a valid comparison of the low total fat and high unsaturated fat diets. The statistical power was not, however, sufficient to exclude a meaningful difference between the diets, as the authors maintain. The confidence intervals indicate that the effect of the two diets on total cholesterol concentration, for example, could easily differ by as much as 7%. To put this in context, the efficacy claimed for the diets when compared with the “control” phase was only 8-9%. The authors' main message, however, had nothing to do with the comparison of the diets but focused on the supposed efficacy …

Editor—Thomas et al report an appreciable prevalence of dysfunctional breathing in adults with asthma and discuss the scope for wider use of breathing therapy.1 Neither Thomas et al nor Keeley and Osman in their editorial2 consider whether such symptoms might occur equally often in the normal population or represent panic attacks and panic disorder, well defined entities common in otherwise healthy people. Without a control group their study is incapable of identifying the prevalence of dysfunctional breathing associated specifically with asthma. Dysfunctional breathing and the hyperventilation syndrome are by no means the same as panic syndromes, but overlap between them may be considerable. Thomas et al acknowledge limitations of the Nijmegen questionnaire.3 This instrument cannot differentiate the “chimeric” hyperventilation syndrome from panic attacks and panic disorder. The 16 items in the Nijmegen questionnaire include “anxiety,” “feeling tense,” and nine of the 13 panic attack symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised (DSM-III-R). The questionnaire was not defined to attempt to make this distinction. A 23% lifetime prevalence of spontaneous panic attacks has been reported in patients with asthma.4 This figure is not dissimilar to the 29% of asthmatic patients labelled by Thomas et al as having experienced dysfunctional breathing and again suggests appreciable overlap. The lifetime prevalence of asthmatics meeting DSM-III-R criteria for panic disorder in the same study was 9.7%4. We reported a significant excess of panic attacks and panic disorder among primary care and hospital patients with hypertension compared with matched normotensive people, and 202 of 287 people who had experienced panic attacks related “shortness of breath” or “difficulty catching breath” as symptoms in their worst panic attack.5 The relation of history of panic attacks to a patient's sex in our sample was strikingly similar to that reported for dysfunctional breathing1, with a significant excess in female patients of around 15% in both studies. The importance of considering panic disorder in a discussion of dysfunctional breathing lies in the availability of treatment of proved efficacy. Thomas et al limit their consideration of therapeutic intervention to breathing therapy. In a patient with recurrent difficult breathing and history suggestive of panic disorder, a much broader range of treatment, from tricyclic antidepressants and selective serotonin reuptake inhibitors to cognitive therapy, may be effective. Failure to identify panic attacks or panic disorder may deprive patients of valuable treatment options, some of which can be instigated in primary care.

Editor—We have suggested that aspirin for primary prevention is safe and worthwhile when the estimated 10 year coronary risk is >15%, provided that any hypertension is controlled.1 This conclusion comes from conservative interpretation of a meta-analysis examining the balance of benefit and risk in four large randomised controlled trials of aspirin for primary prevention, and fully supports recommendations in the Joint British Societies and British Hypertension Society guidelines.2 One assumption central to this analysis, and to these guidelines, is that relative risk reduction by aspirin is constant, so that the magnitude of benefit from aspirin is determined by pretreatment coronary risk. Unfortunately, Meade et al did not examine this assumption in their subgroup analysis of the thrombosis prevention trial.3 Rather, they present subgroup analyses according to individual risk factors (systolic blood pressure, age, and cholesterol concentration). These analyses are not really apposite to the guidelines and may even be misleading. For example, their results suggest little benefit (6% reduction in coronary heart disease) or even harm (8% increase in all cardiovascular events) from aspirin when systolic blood pressure exceeds 145 mm Hg. In the physicians' study in the United States there was a substantial (35%) reduction in coronary events at systolic blood pressure >150 mm Hg.4 In the hypertension optimal treatment study, men with hypertension that was controlled from 168/106 mm Hg to an average of 140/83 mm Hg, which is still “high normal,” had a coronary reduction of 42% (P=0.001) and a 13% reduction in all cardiovascular events.5 The important point is that subgroup analysis of the thrombosis prevention trial is certainly not representative of all the trial evidence available. Similar discrepancies are present in the findings for age. At age 65 and over this subgroup analysis suggests a 29% increase in coronary heart disease, but a 41% reduction in stroke, with aspirin. As the authors note, this is totally inconsistent with the physicians' study, which showed coronary reductions of 44% at ages 60-69 and 41% at ages 70-84.4 In the hypertension optimal treatment study, treated hypertensive patients aged 65 and over had reductions in coronary heart disease of 38% and all cardiovascular events by 21%.5 The treatment policy for aspirin for primary prevention should be based on all the trial evidence and estimation of absolute risk of coronary heart disease,2 not on subgroup analysis of a single trial or on a single coronary risk factor.

Summary The association between haemospermia and hypertension was examined in a case-control study comparing 5 hypertensive patients with haemospermia to 20 age-matched hypertensive men. Patients with haemospermia had much higher blood pressures than hypertensive controls (200/131 mmHg vs 147/90 mmHg; P < 0.0005/P < 0.0001), higher left ventricular voltage on ECG (P < 0.02), and higher concentrations of serum creatinine, proteinuria and renovascular disease (all P = 0.06 vs controls). Haemospermia is associated with severe uncontrolled hypertension. It is not, however, associated with hypertension per se, as the prevalence of hypertension in published series of patients with haemospermia is no higher than that expected in the general population. Men presenting with haemospermia should have their blood pressure measured carefully as they may require antihypertensive treatment urgently.

Editor—Unwin et al highlight the fact that several widely available guidelines for the management of hyperlipidaemia give conflicting advice for the primary prevention of cardiovascular disease.1 Some of the issues deserve further scrutiny. The New Zealand guidelines are based entirely on the ratio of total to high density lipoprotein cholesterol concentrations for calculation of the absolute risk of cardiovascular disease over five years.2 The American national cholesterol education program, however, clearly says that it does not recommend use of the ratio of either total or low density lipoprotein cholesterol to high density lipoprotein cholesterol3; instead it recommends use of the absolute high and low density lipoprotein cholesterol concentrations. The rationale behind this is that these concentrations are independent risk factors with different determinants; combining them into a single number conceals information about either or both, which might be important for making clinical decisions. A patient with raised total, high density lipoprotein, and low density lipoprotein cholesterol concentrations (a common clinical problem) falls into either the low risk category or the high risk category depending on whether the ratio or absolute values are used. The New Zealand guidelines,2 guidelines of the European Atherosclerosis Association,4 and Sheffield tables5 are based largely on age and sex, unlike the guidelines of the American programme,3 which are not; the American guidelines mention, however, that the risk is higher in men than in women. Use of these guidelines would therefore be associated with the highest number of patients requiring antilipid treatment. Only the American guidelines give clear guidance on when measurement of high density lipoprotein cholesterol is indicated in patients with hyperlipidaemia. Measurement of this concentration is labour intensive and expensive and therefore has major implications for laboratories. The New Zealand guidelines necessitate measurement of high density lipoprotein cholesterol in all patients, which would increase the cost substantially. Financial implications may be an important factor for NHS trusts deciding on their policy for managing hyperlipidaemia. Patients are often bewildered when different doctors give them conflicting advice about antilipid treatment. Just as too much of anything is undesirable, too many guidelines end up confusing both patients and doctors.

Editor—Miettinen and colleagues identify a subgroup of Finnish patients with high cholestanol ratios who gained no benefit from statin treatment.1 They suggest that such patients have a low rate of cholesterol synthesis but a high rate of cholesterol absorption and that drugs that block the synthesis of cholesterol therefore do not improve survival. Surprisingly, they presented no data on the falls in serum cholesterol concentrations observed with simvastatin treatment within each cholestanol quarter. This information is essential to fully understand the link between high cholestanol ratio and the smaller reduction in relative risk with simvastatin. It would also be interesting to know whether the balance between cholesterol absorption and synthesis as measured by the cholestanol ratio accounts for a big part of the variability between patients in the response of serum cholesterol concentrations to simvastatin. The authors do not comment on the relatively low (21%) relative risk reduction by simvastatin in the Finnish patients. This seems much smaller than the 34% risk reduction seen in all patients in the Scandinavian simvastatin survival study.2 Is this due to the different definition of major coronary events used in this analysis or did Finnish patients do less well than those in other countries?

1 Consecutive medical inpatients expected to benefit from a theophyllinate were treated with sustained-release aminophylline in a protocol conforming with ordinary practice. Of 16 patients, five had toxicity with aminophylline 450 mg daily, and a further three with 900 mg daily. Toxicity was serious in three patients. 2 Toxicity was significantly less common in cigarette smokers, and was related to higher plasma theophylline concentrations. However, there was a large overlap between concentrations associated with toxicity (as low as 9 micrograms/ml) and the accepted therapeutic range (5-20 micrograms/ml). Most patients with toxicity had theophylline levels within the therapeutic range. 3 For the same dose of aminophylline there was sevenfold variation between patients in plasma theophylline, with higher concentrations in non-smokers, infrequent alcohol users, older patients, those with left ventricular failure and those with lower serum transaminases. There variables could not be separated completely because of the small number of observations. 4 A nomogram for aminophylline dosage or monitoring of serum theophylline levels would have prevented little of the toxicity observed in these patients, although these measures would ensure that therapeutic concentrations were attained, and might prevent life-threatening toxicity.

Summary We describe three patients who developed severe disseminated intravascular coagulation associated with large ventricular mural thrombi shortly after presenting with acute myocardial infarction. To our knowledge this association has not been reported before.

Summary It has been proposed that idiopathic retroperitoneal fibrosis may be a consequence of ‘healed’ retroperitoneal lesions of systemic Weber-Christian disease. However ureteric obstruction which is the hallmark of idiopathic retroperitoneal fibrosis, has not been described in systemic Weber-Christian disease. We report a patient with systemic Weber-Christian disease who, during a relapse, developed bilateral ureteric obstruction which resolved when the Weber-Christian disease remitted. The radiological appearances were consistent with a diagnosis of idiopathic retroperitoneal fibrosis, but the clinical course was slightly atypical in that the ureteric obstruction resolved completely and rapidly. Ureteric obstruction can complicate systemic Weber-Christian disease and this observation gives support to the hypothesis that idiopathic retroperitoneal fibrosis is related to systemic Weber-Christian disease.

The coronary care unit at RNH Haslar is described, the management of patients outlined, and the results of treatment of 98 consecutive cases of acute myocardial infarction over a fifteen month period reported. As regards characteristics of the patients, extent and site of myocardial infarction, incidence of complications, mortality and causes of death, the results are generally comparable to those of large published series. The incidence of venous thrombosis, pulmonary embolism and supraventricular arrhythmias was perhaps higher than reported experience, and consequently some changes in management are suggested.There is little hope in the foreseeable future of a substantial reduction in mortality from myocardial failure, complete heart block, or by preventing late sudden deaths. Effective treatment of ventricular fibrillation, and possibly its prevention, remain the cornerstones of coronary care, and undoubtedly reduce the hospital mortality of acute myocardial infarction. It is essential that a member of staff competent to defibrillate immediately is present in the unit at all times.It is concluded that a purpose-built coronary care unit, sophisticated monitoring or alarm systems, and highly trained staff are not essential to provide effective coronary care.