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 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.

Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials.

OBJECTIVE: To quantify the incremental effect of combining blood pressure-lowering drugs from any 2 classes of thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers over 1 drug alone and to compare the effects of combining drugs with doubling dose. METHODS: Meta-analysis of factorial trials in which participants were randomly allocated to 1 drug alone, another drug alone, both drugs together, or a placebo. RESULTS: We identified 42 trials (10,968 participants). With a thiazide used alone, the mean placebo-subtracted reduction in systolic blood pressure was 7.3 mm Hg and 14.6 mm Hg combined with a drug from another class. The corresponding reductions were 9.3 mm Hg and 18.9 mm Hg with a beta-blocker, 6.8 mm Hg and 13.9 mm Hg with an angiotensin-converting enzyme, and 8.4 mm Hg and 14.3 mm Hg with a calcium channel blocker. The expected blood pressure reduction from 2 drugs together, assuming an additive effect, closely predicted the observed blood pressure reductions. The ratios of the observed to expected incremental blood pressure reductions from combining each class of drug with any other over that from 1 drug were, respectively, for thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers: 1.04 (95% confidence interval [CI], 0.88-1.20), 1.00 (95% CI, 0.76-1.24), 1.16 (95% CI, 0.93-1.39), and 0.89 (95% CI, 0.69-1.09); the overall average was 1.01 (95% CI, 0.90-1.12). Comparison of our results with those of a published meta-analysis of different doses of the same drug showed that doubling the dose of 1 drug had approximately one fifth of the equivalent incremental effect (0.22 [95% CI, 0.19-0.25]). CONCLUSION: Blood pressure reduction from combining drugs from these 4 classes can be predicted on the basis of additive effects. The extra blood pressure reduction from combining drugs from 2 different classes is approximately 5 times greater than doubling the dose of 1 drug.

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.

Vitamin D supplementation and the prevention of fractures and falls: results of a randomised trial in elderly people in residential accommodation.

OBJECTIVES: To determine whether vitamin D supplementation reduces the risk of fracture or falls in elderly people in care home accommodation. DESIGN: A randomised controlled trial of cluster design. SETTING AND SUBJECTS: 223 Residential units (mainly identical 30-bedded units), within 118 homes for elderly people throughout Britain, with 3,717 participating residents (76% women, average age 85 years). The units provided mainly or entirely residential care (35% of residents), nursing care (42%) or care for elderly mentally infirm (EMI) residents (23%). METHODS: Participants were randomly allocated by residential unit (cluster design) to a treated group offered ergocalciferol 2.5 mg every 3 months (equivalent to a daily dose of 1,100 IU), or to a control group. Fractures were reported by staff and confirmed in hospital, and routinely collected data on reported falls were obtained. RESULTS: After median follow-up of 10 months (interquartile range 7-14 months), 64 (3.6%) of 1,762 vitamin D-treated residents and 51 (2.6%) of 1,955 controls had one or more non-vertebral fractures, and 24 (1.3%) and 20 (1.0%), respectively, had a hip fracture. The proportion reporting at least one fall was 44% in vitamin D-treated and 43% in control residents. The differences between the vitamin D and control groups were not statistically significant. The incidence of all non-vertebral fractures in the care homes (3.2% per year) and of hip fractures (1.1% per year) was low, similar to rates in elderly people in sheltered accommodation, and the pre-treatment serum 25-hydroxy vitamin D concentration was high [median 47 nmol/l, measured in a 1% (n = 18) sample]. CONCLUSIONS: We found no evidence that vitamin D prevents fractures or falls in elderly people in care home accommodation.

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.