Lawrence E. Ramsay

Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials

OBJECTIVE To determine the cardiovascular and coronary risk thresholds at which aspirin for primary prevention of coronary heart disease is safe and worthwhile. DESIGN Meta-analysis of four randomised controlled trials of aspirin for primary prevention. The benefit and harm from aspirin treatment were examined to determine: (1) the cardiovascular and coronary risk threshold at which benefit in prevention of myocardial infarction exceeds harm from significant bleeding; and (2) the absolute benefit expressed as number needed to treat (NNT) for aspirin net of cerebral haemorrhage and other bleeding complications at different levels of coronary risk. MAIN OUTCOME MEASURES Benefit from aspirin, expressed as reduction in cardiovascular events, myocardial infarctions, strokes, and total mortality; harm caused by aspirin in relation to significant bleeds and major haemorrhages. RESULTS Aspirin for primary prevention significantly reduced all cardiovascular events by 15% (95% confidence interval (CI) 6% to 22%) and myocardial infarctions by 30% (95% CI 21% to 38%), and non-significantly reduced all deaths by 6% (95% CI −4% to 15%). Aspirin non-significantly increased strokes by 6% (95% CI −24% to 9%) and significantly increased bleeding complications by 69% (95% CI 38% to 107%). The risk of major bleeding balanced the reduction in cardiovascular events when cardiovascular event risk was 0.22%/year. The upper 95% CI for this estimate suggests that harm from aspirin is unlikely to outweigh benefit provided the cardiovascular event risk is 0.8%/year, equivalent to a coronary risk of 0.6%/year. At coronary event risk 1.5%/year, the five year NNT was 44 to prevent a myocardial infarction, and 77 to prevent a myocardial infarction net of any important bleeding complication. At coronary event risk 1%/year the NNT was 67 to prevent a myocardial infarction, and 182 to prevent a myocardial infarction net of important bleeding. CONCLUSIONS Aspirin treatment for primary prevention is safe and worthwhile at coronary event risk ⩾ 1.5%/year; safe but of limited value at coronary risk 1%/year; and unsafe at coronary event risk 0.5%/year. Advice on aspirin for primary prevention requires formal accurate estimation of absolute coronary event risk.

Oxidation Phenotype — A Major Determinant of Metoprolol Metabolism and Response

GENETIC polymorphism in the oxidative metabolism of debrisoquine1 is largely responsible for individual differences in its plasma concentration and antihypertensive effect.2 Poor hydroxylators have...

Is the Framingham risk function valid for northern European populations? A comparison of methods for estimating absolute coronary risk in high risk men

Objective To examine the validity of estimates of coronary heart disease (CHD) risk by the Framingham risk function, for European populations. Design Comparison of CHD risk estimates for individuals derived from the Framingham, prospective cardiovascular Münster (PROCAM), Dundee, and British regional heart (BRHS) risk functions. Setting Sheffield Hypertension Clinic. Patients—206 consecutive hypertensive men aged 35–75 years without preexisting vascular disease. Results There was close agreement among the Framingham, PROCAM, and Dundee risk functions for average CHD risk. For individuals the best correlation was between Framingham and PROCAM, both of which use high density lipoprotein (HDL) cholesterol. When Framingham was used to target a CHD event rate > 3% per year, it identified men with mean CHD risk by PROCAM of 4.6% per year and all had CHD event risks > 1.5% per year. Men at lower risk by Framingham had a mean CHD risk by PROCAM of 1.5% per year, with 16% having a CHD event risk > 3.0% per year. BRHS risk function estimates of CHD risk were fourfold lower than those for the other three risk functions, but with moderate correlations, suggesting an important systematic error. Conclusion There is close agreement between the Framingham, PROCAM, and Dundee risk functions as regards average CHD risk, and moderate agreement for estimates within individuals. Taking PROCAM as the external standard, the Framingham function separates high and low CHD risk groups and is acceptably accurate for northern European populations, at least in men.

Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquin metabolizers

The hypothesis that variability in metoprolol metabolism stereoselectivity is related to debrisoquin oxidation phenotype was tested in six extensive (EM) and six poor (PM) debrisoquin metabolizers. In EM, plasma AUCs for (S)‐metoprolol were 35% higher than for (R)‐metoprolol, whereas in PM, AUCs for (S)‐metoprolol were lower than for (R)‐metoprolol. AUCs for total metoprolol correlated with the ratio of (S)‐ to (R)‐metoprolol AUC. The renal clearance of metoprolol was also stereoselective but to the same extent in both EM and PM. Findings suggest that the enzyme system responsible for polymorphic oxidation of the debrisoquin‐type is stereoselective. The relation between log total metoprolol plasma concentration and response (β‐blockade) was shifted to the right in PM relative to EM, which is compatible with a difference in pharmacologic activity of metoprolol enantiomers. Kinetic predictions based on total drug measurements will tend to overestimate dynamic differences between EM and PM, but the magnitude of the error is relatively small, and, in absolute terms, there is a large difference in pharmacologic activity between the phenotypes (β‐blockade at 24 hr: EM = 5.3 ± 5.6%; PM = 18.9 ± 3.8%).

Treatment of hypertension in the elderly

Purpose: The outcome of treatment in elderly hypertensives is examined in six major randomized controlled trials. Thiazide diuretics were first- or second-line drugs in each, and P-blockers were first- or second-line drugs in four. Data identification: All compared immediate active treatment, with drugs added stepwise until blood pressure was controlled, versus withholding antihypertensive treatment unless blood pressure exceeded predetermined safety levels. Results of data analysis: Because placebo-treated patients required active treatment and actively treated patients required more than one drug, benefits were underestimated and the comparisons were not of single drugs with each other or with placebo. The incidence of fatal stroke was reduced by 33%, of fatal coronary events by 26% and cardiovascular mortality by 22%. Because cardiovascular risk varied among the trial populations, the absolute benefit from treatment varied markedly. Conclusions: In trials representative of unselected patients, treatment of diastolic hypertension might prevent cardiovascular complications in 1.4-2.2% of patients each year and fatal cardiovascular complications in 0.5-1.3% each year. In isolated systolic hypertension, treatment might prevent cardiovascular complications in 1.1% of patients each year. Generally, diuretic treatment proved superior to treatment with P-blocker, and drugs of both types were well tolerated. There is a strong case for treating elderly hypertensives with a diuretic-based regimen.

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.

Cost effectiveness of HMG-CoA reductase inhibitor (statin) treatment related to the risk of coronary heart disease and cost of drug treatment

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 (< 3.0% per year) is less cost effective and unlikely to be affordable at current prices and levels of health service funding. As the cost of statins falls, primary prevention at lower risk levels becomes more cost effective. However, the large volume of treatment needed will remain a major problem.

Effect of coffee and cigarette smoking on the blood pressure of untreated and diuretic-treated hypertensive patients

Patients with mild hypertension who habitually smoked cigarettes and consumed caffeine were examined after they abstained from caffeine and cigarettes overnight. Their mean blood pressure (147/89 mm Hg) was substantially lower than values recorded in the clinic (164/102 mm Hg) and remained so when they continued to abstain (149/94 mm Hg at two hours). Smoking two cigarettes (3.4 mg nicotine) elevated blood pressure by 10/8 mm Hg, but for only 15 minutes. Drinking coffee (200 mg caffeine) elevated blood pressure by up to 10/7 mm Hg between one and two hours. Combined coffee ingestion and cigarette smoking caused a sustained rise in blood pressure from 5 to 120 minutes to levels similar to those measured in the clinic (162/102 mm Hg at two hours). Similar results were obtained in thiazide-treated patients. The interaction of coffee and cigarettes on blood pressure, but not on pulse rate, was significant. The pressor effect of cigarette smoking and caffeine ingestion in combination may be important in the evaluation of patients with mild hypertension.

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.

beta blockade and intermittent claudication: placebo controlled trial of atenolol and nifedipine and their combination.

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.