Interpretation of the evidence for the efficacy and safety of statin therapy.

This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse effects reflect a failure to recognise the limitations of other sources of evidence about the effects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The absolute benefits of statin therapy depend on an individual's absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an effective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events from occurring in about 1000 patients (ie, 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (ie, 5% absolute benefit) who are at increased risk but have not yet had a vascular event (primary prevention). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefits would accrue with more prolonged therapy, and these benefits persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy-ie, adverse effects of the statin-are myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50-100 new cases of diabetes, and 5-10 haemorrhagic strokes. However, any adverse impact of these side-effects on major vascular events has already been taken into account in the estimates of the absolute benefits. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50-100 patients (ie, 0·5-1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating.

A 16-week, randomized, double-blind, placebo-controlled, crossover trial to quantify the combined effect of an angiotensin-converting enzyme inhibitor and a beta-blocker on blood pressure reduction.

BACKGROUND: Although beta-blockers and angiotensin-converting enzyme (ACE) inhibitors are often used together, there is a lack of quantitative evidence for the efficacy of this combination in reducing blood pressure (BP). OBJECTIVE: The aim of this randomized, double-blind, placebo-controlled, crossover study was to quantify the combined effect of a beta-blocker (atenolol) and an ACE inhibitor (lisinopril) in lowering BP. METHODS: Participants who were > or = 40 years of age and enrolled in the hypertension or anticoagulation clinics at St. Bartholomew's Hospital, London, United Kingdom, were randomized to 3 consecutive 4-week treatments consisting of atenolol 25 mg plus placebo, lisinopril 5 mg plus placebo, and atenolol 25 mg plus lisinopril 5 mg, plus a period of 2 placebos. At the end of each period, seated BP was measured in the right arm using electronic monitors. RESULTS: The mean placebo-adjusted peak BP reductions among the 47 participants (mean age, 62 [range 42-82] years; 75% male; 70% white/30% Asian; mean baseline BP, 145/82 mm Hg) who completed all 4 periods were significantly greater with the combination of both drugs than with either drug alone (P < 0.001). The systolic reductions were 22.9 mm Hg with combination treatment, 16.1 mm Hg with atenolol treatment, and 12.5 mm Hg with lisinopril treatment, and the diastolic reductions were 13.9, 9.8, and 6.8 mm Hg, respectively. The BP-lowering effect of the 2 drugs together was similar to that expected from the sum of each alone, allowing for the reduced effect of 1 drug given the lower pretreatment BP due to the other. The incremental systolic BP reduction from the 2 drugs together compared with 1 alone was 79% (95% CI, 54%-126%) of the expected additive effect, 88% (95% CI, 58%-130%) for diastolic BP, and 84% (95% CI, 65%-118%) for the mean of systolic and diastolic BP. CONCLUSIONS: The combination of the beta-blocker atenolol 25 mg plus the ACE inhibitor lisinopril 5 mg was associated with a significantly greater decrease in BP compared with either alone. The BP reduction with the combination treatment was similar to and statistically consistent with the 2 drugs having additive effects. Clinical Trials Identification Number: ISRCTN97280940.

Headaches and the treatment of blood pressure: results from a meta-analysis of 94 randomized placebo-controlled trials with 24,000 participants.

BACKGROUND: Uncertainty exists over whether blood pressure-lowering drugs prevent headache. METHODS AND RESULTS: A meta-analysis was carried out of the 94 randomized placebo-controlled trials of 4 different classes of blood pressure-lowering drugs (thiazides, beta-blockers, ACE inhibitors, and angiotensin II receptor antagonists) in fixed doses in which data on headache were reported. There were 17,641 participants who were allocated blood pressure-lowering drugs and 6603 who were allocated placebo. Treatment lowered systolic and diastolic blood pressures by 9.4 and 5.5 mm Hg, respectively, on average. One third fewer people on average reported headache in the treated groups (8.0%) than the placebo groups (12.4%) (odds ratio, 0.67; 95% CI, 0.61 to 0.74; P<0.001). About 1 in 30 treated persons benefited by having headache prevented. The prevalence of headache was reduced (P<0.001) in trials of each of the 4 classes of drugs. CONCLUSIONS: Our results show that blood pressure-lowering drugs prevent a significant proportion of headaches. That this effect is seen with pharmacologically unrelated classes of drugs indicates that it is likely to be due to the reduction in blood pressure per se, the only recognized action that the drugs have in common. This in turn indicates that high blood pressure is a cause of headache, but this conclusion is not supported by observational studies of blood pressure and headache. The uncertainty over whether high blood pressure causes headache does not, however, detract from the practical benefits of the use of blood pressure-lowering drugs in preventing headaches and cardiovascular disease.

Blood pressure and the global burden of disease 2000. Part 1: estimates of blood pressure levels.

OBJECTIVE: To provide global estimates of blood pressure by age and sex for adults aged > or = 30 years, by WHO subregion. DESIGN AND METHODS: Data were obtained from studies identified in a literature review of population-based surveys. These were complemented by data from MONICA and INTERSALT studies. Estimates of the shape of the age-systolic blood pressure (SBP) association were made from survey data utilizing parametric and non-parametric analyses. A linear sex-specific association of SBP with age was demonstrated from 30 to 70 years in females and 20 to 70 years for males in each subregion. Mean age- and sex-specific estimates of SBP were estimated for each WHO subregion separately, based on study and country-weighted SBP data. RESULTS: Analyses were based on data from about 230 surveys and over 660 000 participants. Age-specific mean SBP values ranged from 114 to 164 mmHg for females, and 117-153 mmHg for males. Females typically had lower SBP levels than males in the 30-44-year age groups, but in all subregions, SBP levels rose more steeply with age for females than males. Therefore, SBP levels in those aged > or = 60 years tended to be higher in females. Subregions with consistently high mean SBP levels included parts of eastern Europe and Africa. Mean SBP levels were lowest in south-east Asia and parts of the western Pacific. CONCLUSIONS: These global estimates of blood pressure by age, sex and subregion show considerable variation in estimated levels. The lack of data in developing countries is substantial, and this is an important limitation given the role of blood pressure in increasing cardiovascular disease levels.

Blood pressure and the global burden of disease 2000. Part II: estimates of attributable burden.

OBJECTIVES: To provide estimates of the global burden of disease attributable to non-optimal blood pressure by age and sex for adults aged > or = 30 years, by WHO subregion. METHODS: Estimates of attributable burden were made using population impact fractions, which used data on mean systolic blood pressure levels, disease burden [in deaths and/or disability-adjusted life years (DALYs)] and relative risk corrected for regression dilution bias. Estimates were made of burden attributable to a population distribution of blood pressure with a mean systolic blood pressure of greater than 115 mmHg. RESULTS: Globally, approximately two-thirds of stroke and one-half of ischaemic heart disease were attributable to non-optimal blood pressure. These proportions were highest in the more developed parts of the world. Worldwide, 7.1 million deaths (approximately 12.8% of the global total) and 64.3 million DALYs (4.4% of the global total) were estimated to be due to non-optimal blood pressure. Overall approximately, two-thirds of the attributable burden of disease occurred in the developing world, approximately two-thirds in the middle age groups (45-69 years) and approximately one-half occurred in those with systolic blood pressure levels between 130 and 150 mmHg. CONCLUSIONS: The burden of non-optimal blood pressure is almost double that of the only previous global estimates, which is largely explained by the correction for regression dilution adopted in these analyses. High blood pressure is a leading cause of global burden of disease, and most of it occurs in the developing world.

Statin safety: a systematic review.

A systematic review of cohort studies, randomized trials, voluntary notifications to national regulatory authorities, and published case reports was undertaken to assess the incidence and characteristics of adverse effects in patients treated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins. For statins other than cerivastatin, the incidence of rhabdomyolysis in 2 cohort studies was 3.4 (1.6 to 6.5) per 100,000 person-years, an estimate supported by data from 20 randomized controlled trials. Case fatality was 10%. Incidence was about 10 times greater when gemfibrozil was used in combination with statins. Incidence was higher (4.2 per 100,000 person-years) with lovastatin, simvastatin, or atorvastatin (which are oxidized by cytochrome P450 3A4 [CYP3A4], which is inhibited by many drugs) than pravastatin or fluvastatin (which are not oxidized by CYP3A4). In persons taking simvastatin, lovastatin, or atorvastatin, 60% of cases involved drugs known to inhibit CYP3A4 (especially erythromycin and azole antifungals), and 19% involved fibrates, principally gemfibrozil. The incidence of myopathy in patients treated with statins, estimated from cohort studies supported by randomized trials, was 11 per 100,000 person-years. For liver disease, randomized trials reported fewer hepatobiliary disorders in patients allocated statins than in those allocated placebo. The notification rate of liver failure to regulatory authorities was about 1 per million person-years of statin use. Randomized trials show no excess of renal disease or proteinuria in statin-allocated participants, and the decline in glomerular filtration rate was smaller with statins than with placebo. Evidence from 4 cohort studies and case reports suggests that statins cause peripheral neuropathy, but the attributable risk is small (12 per 100,000 person-years). No change in cognitive function was found in randomized trials of statins in elderly patients.

The underlying risk of death after myocardial infarction in the absence of treatment.

BACKGROUND: The underlying risk of death in the absence of treatment after a myocardial infarction (MI) is poorly documented. METHODS: Analysis of 23 published studies in which 14 211 patients were followed prospectively after MI; 6817 deaths were recorded. We restricted the analysis to studies in which follow-up was completed by 1980 to quantify the underlying risk in the absence of effective treatments. RESULTS: After a first MI, on average, 23% of patients died before reaching the hospital and another 13% died during hospital admission; these rates increased with age. After hospital discharge cardiovascular mortality was approximately 10% in the first year and 5% per year thereafter, rates that were unrelated to age or sex. The yearly death rate of 5% persisted indefinitely; after 15 years, cumulative cardiovascular mortality was 70%. After a subsequent MI, 33% of patients died before reaching the hospital, and 20% died in hospital. After discharge, cardiovascular mortality was approximately 20% in the first year and 10% per year thereafter, rates again unrelated to age and sex. Approximately a third of all heart disease deaths occurred minutes after the first MI, a sixth during the first hospitalization, and half after a subsequent MI, which could occur many years after the first. CONCLUSIONS: In persons with a history of MI, cardiovascular mortality in the absence of treatment is high-5% per year after a first MI and 10% per year after a subsequent MI, persisting for many years and probably for the rest of a person's life. The high mortality rate emphasizes the need to ensure that everyone who has had an MI, even years previously, receives effective preventive treatment.

Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels.

Foods with plant stanol or sterol esters lower serum cholesterol levels. We summarize the deliberations of 32 experts on the efficacy and safety of sterols and stanols. A meta-analysis of 41 trials showed that intake of 2 g/d of stanols or sterols reduced low-density lipoprotein (LDL) by 10%; higher intakes added little. Efficacy is similar for sterols and stanols, but the food form may substantially affect LDL reduction. Effects are additive with diet or drug interventions: eating foods low in saturated fat and cholesterol and high in stanols or sterols can reduce LDL by 20%; adding sterols or stanols to statin medication is more effective than doubling the statin dose. A meta-analysis of 10 to 15 trials per vitamin showed that plasma levels of vitamins A and D are not affected by stanols or sterols. Alpha carotene, lycopene, and vitamin E levels remained stable relative to their carrier molecule, LDL. Beta carotene levels declined, but adverse health outcomes were not expected. Sterol-enriched foods increased plasma sterol levels, and workshop participants discussed whether this would increase risk, in view of the marked increase of atherosclerosis in patients with homozygous phytosterolemia. This risk is believed to be largely hypothetical, and any increase due to the small increase in plasma plant sterols may be more than offset by the decrease in plasma LDL. There are insufficient data to suggest that plant stanols or sterols either prevent or promote colon carcinogenesis. Safety of sterols and stanols is being monitored by follow-up of samples from the general population; however, the power of such studies to pick up infrequent increases in common diseases, if any exist, is limited. A trial with clinical outcomes probably would not answer remaining questions about infrequent adverse effects. Trials with surrogate end points such as intima-media thickness might corroborate the expected efficacy in reducing atherosclerosis. However, present evidence is sufficient to promote use of sterols and stanols for lowering LDL cholesterol levels in persons at increased risk for coronary heart disease.

Mortality from hypertrophic cardiomyopathy in England and Wales: clinical and screening implications.

OBJECTIVES: Hypertrophic cardiomyopathy is considered a relatively common cause of death in the young. Screening for the disorder has been advocated, but its potential value cannot be assessed because the number of deaths in asymptomatic cases in the general population has not been investigated. We determined the annual number of deaths (and death rates) from hypertrophic cardiomyopathy in England and Wales according to age, sex and the presence or absence of symptoms so that an affected individual's risk of dying from the disorder and the implications of screening could be assessed. METHODS: Ascertainment of all deaths from hypertrophic cardiomyopathy over a 3-year period (1996-1998), using death certification data from the Office of National Statistics. Deaths in people without symptoms were identified from coroner's reports and correspondence with pathologists who conducted the necropsies. RESULTS: There were 184 deaths per year from hypertrophic cardiomyopathy in England and Wales (about 15% of all deaths from cardiomyopathy) of which one third (65) were in people without symptoms. Most (110) of the 184 deaths each year were in people over age 55. Under age 55 there were only 37 deaths each year in asymptomatic people, out of an estimated 60,000 people with the disorder in the population. Of the 37 deaths, 14 (20%) occurred in relation to physical activity and 2 after competitive sport. CONCLUSIONS: In young people without symptoms hypertrophic cardiomyopathy is fairly common (1 in 500) but it rarely causes death; the case-fatality rate is about 6 per 10,000 per year. Current risk estimates from the study of patients in tertiary referral centers or general hospital clinics (420 and 110 deaths per 10,000 per year, respectively) are not applicable to asymptomatic people in the general population; such people, if incidentally identified can be reassured of their low risk of death. Screening would not be worthwhile unless a satisfactory test becomes available that can detect those few cases likely to die.

A change in paradigm: lowering blood pressure in everyone over a certain age.

Dividing people into 'hypertensives' and 'normotensives' is commonplace but problematic. The relationship between blood pressure and cardiovascular disease is continuous. The Prospective Studies Collaboration analysis shows a continuous straight line dose-response relationship across the entire population down to blood pressure levels of 115 mmHg systolic and 75 mmHg diastolic, the confidence limits on the individual data points being sufficiently narrow to exclude even a minor deviation from a linear relationship. Meta-analysis of randomized controlled trials shows that blood pressure-lowering drugs produce similar proportional reductions in risk of coronary heart disease (CHD) and stroke irrespective of pre-treatment blood pressure, down to levels of 110 mmHg systolic and 70 mmHg diastolic. There are also now sufficient trial data to show a statistically significant risk reduction in 'normotensive' people without known vascular disease on entry. The straight line (log-linear) relationship means that the benefit derived from lowering blood pressure is proportional to existing risk, so the decision on whom to treat with blood pressure-lowering drugs should depend on a person's overall absolute risk irrespective of blood pressure. In primary prevention, basing treatment on age alone rather than overall absolute risk entails little loss of efficacy and may be preferred on the basis of simplicity and avoidance of anxiety in telling people they are at elevated risk.