Peter R. Jackson

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.

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.

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.

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.

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.

Altered plasma drug binding in cancer: Role of α1‐acid glycoprotein and albumin

Altered concentrations of serum proteins often accompany malignant disease. The effect of these changes on drug binding was studied with lidocaine, a basic drug, and tolbutamide, an acidic drug. Patients with cancer had increased serum concentrations of the acute‐phase protein α1‐acid glycoprotein (AAG) and lowered serum concentration of albumin. In association with these changes lidocaine binding was increased at all concentrations studied (predialysis concentrations 2, 6, and 10 μg · ml−1) and that of tolbutamide was decreased at the highest concentration (200 μg · ml−1). Not all of the increase in lidocaine binding was explicable on the basis of increased serum AAG concentration. Estimation of binding parameters with a model with two independent sites showed increased affinity at the high affinity site in cancer patients with no change in the calculated number of binding sites. Therefore, in cancer there is increased lidocaine binding in association with increased AAG concentrations. We also record the novel observation of a change in the intrinsic properties of the high affinity binding site.

Depleting Serotonin Enhances both Cardiovascular and Psychological Stress Reactivity in Recovered Patients with Anxiety Disorders

Abstract: Serotonin-promoting drugs show cardioprotective properties in patients with anxiety or depression, but it is not known if this is a direct effect of increasing serotonin. We aimed to characterize the effect of serotonin manipulation through acute tryptophan depletion on cardiovascular and psychological responses to stress challenge in recovered patients with anxiety disorders. In 27 recovered patients with anxiety disorders (panic disorder treated by selective serotonin reuptake inhibitors (SSRIs) or cognitive behavioral therapy, social anxiety disorder treated by SSRIs), we performed a double-blind randomized crossover study. On 2 separate days, the subjects ingested an acute tryptophan-depleting (aTD) or nondepleting (nD) drink in random order and underwent a stress challenge at time of maximum depletion. Systolic blood pressure (P = 0.007; diff = 9.0 mm Hg; 95% confidence interval (CI), 2.6-15.3 mm Hg) and diastolic blood pressure (P = 0.032; diff = 5.7 mm Hg; 95% CI, 0.6-10.9 mm Hg) responses to stress were significantly greater under aTD than nD, as were the psychological responses to stress (for Spielberger state anxiety, difference in stress response between aTD and nD = 7.11; P = 0.025). Blood pressure responses to stress showed no correlation with psychological responses. The significant increases in acute stress sensitivity in both cardiovascular and psychological domains on serotonin depletion suggest that serotonin is involved in the control of both cardiovascular and psychological aspects of the acute stress response. The lack of correlation in the difference between aTD and nD conditions in cardiovascular and psychological responses suggests that serotonin may have distinct effects on these 2 domains, rather than the cardiovascular responses being merely a secondary consequence of psychological changes.

Treatment of anxiety and depressive disorders in patients with cardiovascular disease.

What role do selective serotonin reuptake inhibitors have in treating psychiatric morbidity in patients with cardiovascular disease? This review discusses the safety and efficacy of various antidepressants in this group of patients and their potential for improving cardiovascular outcomes Anxiety and depressive disorders are common in the general population and are particularly prevalent in patients with cardiovascular disease (box 1).1–3 w1-w3 We reviewed evidence for a biological explanation for this association and for drug treatment and psychotherapy for psychiatric morbidity in patients with cardiovascular disease. We systematically searched Medline (1966 to August 2003 through Ovid) and Embase (1980 to October 2002) for all relevant English language articles. Firstly, we entered terms and text words including myocardial infarction, angina, hypertension, stroke, cerebrovascular, and poststroke. Secondly, we used the terms and text words “SSRIs”, “serotonin reuptake inhibitors”, and individual drug names. The searches were combined and relevant articles retrieved. The reference lists were searched for other potentially relevant articles. Much evidence links depression with coronary artery disease and hypertension; 16% of patients assessed seven days after myocardial infarction had symptoms consistent with a major depressive episode.1 w1 w2 Several studies have shown a link between anxiety disorders and coronary heart disease and between anxiety disorders and hypertension.2 Associations between psychiatric morbidity and cardiovascular disease could simply be attributed to patients being psychologically undermined after diagnosis but this does not explain prospective studies showing excess incidence of cardiovascular problems or poorer cardiovascular outcome in patients with depression and anxiety disorders. One study reported a 3.5-fold increase in mortality of depressed patients compared with non-depressed patients within six months of myocardial infarction.1 Depression has been associated with the development of cardiovascular complications in patients with hypertension, and several prospective studies have suggested a link between anxiety disorders and …

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.