Statins for primary prevention: at what coronary risk is safety assured?

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Population implications of lipid lowering for prevention of coronary heart disease: data from the 1995 Scottish health survey.

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 < 60 years). SUBJECTS: Random stratified sample of 3963 subjects aged 35-64 years from the Scottish health survey 1995. RESULTS: For secondary prevention 7.8% (95% confidence interval (CI) 6.9% to 8.6%) of the population with cholesterol >/= 5.0 mmol/l would benefit from statins. For primary prevention, the prevalence of people at CHD risk 30%, 20%, 15%, and 6% over 10 years is 1.5% (95% CI 1.2% to 1.9%), 5.4% (95% CI 4.7% to 6.1%), 9.7% (95% CI 8.8% to 10.6%), and 32.9% (95% CI 31.5% to 34.4%), respectively. At projected CHD risk 20% over 10 years, 12.4% (95% CI 11.4% to 13.5%) would be treated with statins. Removing the 5.0 mmol/l cholesterol threshold makes little difference to population prevalence at high CHD risk. CONCLUSIONS: Statin treatment would be required for 7.8% of the population for secondary prevention. For primary prevention, among other factors, guidelines should take into account the number of patients needing treatment at different levels of CHD risk when choosing the CHD risk to target. The analysis supports a policy of targeting treatment at CHD risk 30% over 10 years as a minimum, as recommended in current British guidelines, with a move to treating at CHD risk 15% over 10 years as resources permit.

Is coronary risk an accurate surrogate for cardiovascular risk for treatment decisions in mild hypertension? A population validation.

OBJECTIVE: To examine the relationship between coronary (CHD) and cardiovascular (CVD) risk in patients with uncomplicated mild hypertension and to determine the accuracy of using CHD risk > or = 15% over 10 years to identify for antihypertensive treatment those patients with CVD risk > or = 20% over 10 years as advised in recent British guidelines. DESIGN: Comparison of decisions made using CHD risk > or = 15% over 10 years calculated by the Framingham risk function and estimated using a simple table with CVD risk > or = 20% over 10 years. SETTING: British population. SUBJECTS: People aged 35-64 years with uncomplicated mild systolic hypertension (SBP 140-159 mmHg, n = 624) from the 1995 Scottish Health Survey. MAIN OUTCOME MEASURES: Relationship between CHD and CVD risk. Sensitivity, specificity, positive and negative predictive values (PPV and NPV). RESULTS: CHD risk 15% over 10 years was equivalent to CVD risk 21% over 10 years. Exact CHD risk > or = 15% over 10 years had sensitivity 79%, specificity 98%, PPV 94% and NPV 93% in detecting CVD risk > or = 20% over 10 years. Use of the table to estimate CHD risk > or = 15% over 10 years gave sensitivity 88%, specificity 90%, PPV 76% and NPV 95%. CONCLUSION: CHD risk appears acceptably accurate for targeting treatment in mild hypertension. The risk assessment table, which slightly overestimates CHD risk, was more sensitive in identifying patients with CVD risk > or = 20% over 10 years and may be preferable to using exact CHD risk. European guidelines which suggest targeting treatment for mild hypertension at CHD risk > or = 20% over 10 years are over-conservative compared with British guidelines.

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.

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

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 >/=30% over 10 years; aspirin treatment when the risk is >/=15% over 10 years; and the treatment of mild hypertension when the cardiovascular risk is >/=20% over 10 years. 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.

Implication of recent trials with b-hydroxy-b-methylglutaryl coenzyme A reductase inhibitors for hypertension management.

BACKGROUND: There is broad agreement that statin treatment should be targeted at absolute coronary heart disease (CHD) risk but no consensus on the level of risk to target. We have examined the implications of adopting three different treatment policies for the management of hypertensive patients in the UK using data from treated hypertensives aged 35-69 years included in the Health Survey for England (1993). METHODS: We calculated the proportion of hypertensive patients with existing atherosclerotic cardiovascular disease requiring statin treatment for secondary prevention of CHD. For those without atherosclerotic cardiovascular disease (primary prevention), we estimated CHD risk from the Framingham equation and examined the proportion with CHD risk exceeding thresholds of 4.5, 3 and 1.5% per year. RESULTS: Twenty-one percent of treated hypertensives would require statin treatment for secondary prevention of CHD. When the CHD event threshold for statin treatment was set at > or =4.5% per year [equivalent to a number needed to treat (NNT) in 5 years of 13] a further 0.6% of hypertensive patients were identified for treatment; at a threshold of 3.0% per year (NNT = 20) 5.5% of patients were identified for primary prevention; and at a threshold of 1.5% per year (NNT = 40) 28.5% of patients were identified for primary prevention. CONCLUSIONS: Those needing secondary prevention are first priority for statins and 21% of hypertensive patients will require treatment Formulation of guidelines for primary prevention should take into account the NNT; the proportion of patients targeted for treatment; the cost-effectiveness and the total cost of treatment. Current British guidance will entail treating an additional 5.5% of hypertensive patients for primary prevention and therefore 27% of hypertensive patients.

Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients.

AIMS: To investigate whether an interaction between diltiazem and the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin may enhance the cholesterol-lowering response to simvastatin in diltiazem-treated patients. METHODS: One hundred and thirty-five patients attending the Sheffield hypertension clinic who started consecutively on simvastatin for primary or secondary prevention of coronary heart disease (CHD) during the 2 years June, 1996-May 1998 were surveyed. From the clinic records we extracted and recorded absolute and percentage cholesterol responses to the starting dose of simvastatin and coprescription of diltiazem. RESULTS: The cholesterol reduction for the 19 patients on diltiazem was 33.3% compared with 24.7% in the remaining 116 patients (median difference 8.6%, 95% CI 1.1-12.2%, P<0.02). The interindividual variability of cholesterol response to simvastatin was greater for patients not taking diltiazem than for those patients taking diltiazem. The ratio of the variances in response for the nondiltiazem group relative to the diltiazem group was 1.34 at 10 mg simvastatin daily (not significant, 95% CI 0.16-4.11), and 3.42 at 20 mg daily (P<0.01, 95% CI 1.26-7.18). Concurrent diltiazem therapy (P<0.04), age (P=0.001) and starting dose of simvastatin (P=0.002) were found to be significant independent predictors of percentage cholesterol response. CONCLUSIONS: Patients who take both simvastatin and diltiazem may need lower doses of simvastatin to achieve the recommended reduction in cholesterol. The pharmacokinetic and pharmacodynamic aspects of this interaction need further study to confirm an enhanced effect on cholesterol reduction, and exclude an increased risk of adverse events.

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.

Prediction of coronary risk for primary prevention of coronary heart disease: a comparison of methods.

Most recent guidelines advise targeting of lipid lowering for primary prevention at those at high absolute coronary (CHD) risk. We compared the accuracy of five CHD risk assessment methods in identifying such patients: one based on total cholesterol > or = 6.5 mmol/l plus two risk factors, and four based on the Framingham risk function (the European Task Force chart and Sheffield table, both using total cholesterol and the New Zealand chart and modified Sheffield table, both using total: HDL cholesterol ratio) for predicting CHD event risk > or = 2% per year, calculated by an independent risk function, PROCAM, in 126 treated hypertensive men. Cholesterol threshold plus two risk factors had sensitivity 59% and specificity 63%, did not identify some very high-risk patients, and identified very low-risk patients. Framingham-based methods using total cholesterol alone had sensitivity 90-98% and specificity 37-43%, and identified high-risk patients well, but identified some patients at very low risk. Methods based on total: HDL cholesterol ratio had sensitivity 90-98% and specificity 60-63%, and did not identify incorrectly patients at very low CHD risk. Methods based on cholesterol threshold and counting of risk factors are too inaccurate for targeting drug therapy for primary prevention of CHD. Framingham-based methods should incorporate HDL-cholesterol as the total: HDL cholesterol ratio.

Combined inhibition of neutral endopeptidase and angiotensin-converting enzyme by sampatrilat in essential hypertension.

BACKGROUND: The antihypertensive response to angiotensin-converting enzyme (ACE) inhibitors may be attenuated by a compensatory decrease in atrial natriuretic factor production. If so, inhibition of atrial natriuretic factor breakdown by neutral endopeptidase (NEP) may enhance the antihypertensive effects of ACE inhibition. We compared effects of the combined ACE-NEP inhibitor sampatrilat, lisinopril, and placebo on blood pressure, plasma ACE, and renin activity and urinary cyclic guanosine monophosphate (cGMP) of patients with hypertension. METHODS AND RESULTS: After a 4-week placebo run-in period, 124 patients with a mean blood pressure of 162/102 mm Hg were randomized in a double-blind parallel-group design to 1 of 5 treatments, given once daily for 10 days: 50 mg, 100 mg, or 200 mg sampatrilat; 20 mg lisinopril; or placebo. The first dose of sampatrilat did not lower clinic or ambulatory blood pressure. Lisinopril had an immediate antihypertensive effect that differed significantly from all doses of sampatrilat. After 10 days of treatment, sampatrilat lowered clinic and ambulatory blood pressure significantly at all doses, with a trend toward a dose response for systolic ambulatory blood pressure. Sampatrilat inhibited plasma ACE in a dose-dependent fashion but significantly less so than lisinopril on days 1 and 10 of treatment. Lisinopril but not sampatrilat significantly increased plasma renin activity, whereas sampatrilat but not lisinopril significantly increased urinary cGMP excretion. CONCLUSION: The increasing efficacy of sampatrilat compared with lisinopril over 10 days could not be attributed to an increase in plasma ACE inhibition, suggesting that the NEP inhibitor activity of sampatrilat may have contributed to its antihypertensive action. NEP inhibition may enhance the antihypertensive effect of ACE inhibition.