Statins are widely prescribed on the NHS
Guidelines on who is eligible for statins may need to be widened after an international trial found benefits in "healthy" adults, experts say.The study of 17,800 men and women with normal cholesterol levels found rosuvastatin cut deaths from heart attacks and strokes.
Currently statins are offered to people with a moderate to high risk of a cardiovascular "event".
The results are published in the New England Journal of Medicine Published at www.nejm.org November 9, 2008 (10.1056/NEJMoa0807646)
The patients in the trial, funded by AstraZeneca, had cholesterol levels below those usually indicating a need for treatment and had no other signs of heart disease.
These are people who have an intermediate risk and you wouldn't normally prescribe statins for them in the UK
Dr Terry McCormack,
But they did have increased levels of a C-reactive protein, which indicates inflammation in the body and is believed to be a marker of future cardiovascular events.
After an average follow-up of two years, 20mg a day of rosuvastatin was found to have cut cholesterol by 50% and C-reactive protein by 37%.
Overall, the chance of a heart attack, stroke, hospital admission for chest pain or death from cardiovascular disease was cut by 44%, researchers said.
A reduction was even seen in those with the lowest chance of a cardiovascular event over the next decade, they said.
Researchers found a higher incidence of physician-reported diabetes in the statin group but could not explain it as blood glucose levels were similar between those taking rosuvastatin and those taking a dummy pill.
Statins are already prescribed to millions of adults in the UK.
The UK's National Institute of Clinical and Health Excellence (NICE)recommends doctors carry out a risk calculation based on an individual's blood pressure, cholesterol, weight and other risk factors, such as whether or not they smoke.
Those with a 20% risk of a heart attack or stroke in the next 10 years should be prescribed a daily dose of simvastatin - the cheapest of the statin class.
Dr Terry McCormack, a GP in Whitby, North Yorkshire, and ex-chairman of the Primary Care Cardiovascular Society, said the results were "astonishing" and much stronger than he would have expected.He added that NICE should redo their cost-effectiveness calculation on the basis of the latest figures.
"These are people who have an intermediate risk and you wouldn't normally prescribe statins for them in the UK," he said.Professor Peter Sever, an expert in clinical pharmacology at Imperial College in London, said
"It opens up a whole new debate and the trial probably raises more questions than it answers."
the results backed other studies which had shown statins had the same proportional benefit however low an individual's cholesterol.But he added:
"The thing to remember is that the 20% threshold is arbitrary - it is essentially based on economic issues.
"Most nations have a finite pot and if you're going to treat everyone with a 10% risk, that's billions of pounds extra and somewhere along the line someone else is going to miss out."Dr Alan McDougall, from AstraZeneca, said there was "no question" the trial would raise some important issues about statin use but that they would recommend doctors still follow existing guidance.
NICE is due to consult on plans to review their statin guidance shortly.
Background Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment.
Methods We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.
Results The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001),> rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001),> the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001),> any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes.
Conclusions In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681 [ClinicalTrials.gov] .)
Current treatment algorithms for the prevention of myocardial infarction, stroke, and death from cardiovascular causes recommend statin therapy for patients with established vascular disease, diabetes, and overt hyperlipidemia.1,2
However, half of all myocardial infarctions and strokes occur among apparently healthy men and women with levels of low-density lipoprotein (LDL) cholesterol that are below currently recommended thresholds for treatment.Measurement of high-sensitivity C-reactive protein, an inflammatory biomarker that independently predicts future vascular events, improves global classification of risk, regardless of the LDL cholesterol level.3,4,5,6,7,8,9 We have previously shown that statin therapy reduces high-sensitivity C-reactive protein levels10,11 and that among healthy persons,12 patients with stable coronary disease,13 and those with the acute coronary syndrome,14,15,16 the magnitude of the benefit associated with statin therapy correlates in part with the achieved high-sensitivity C-reactive protein level. To date, however, no prospective outcome trial has directly addressed the question of whether apparently healthy persons with levels of LDL cholesterol below current treatment thresholds but with elevated levels of high-sensitivity C-reactive protein might benefit from statin therapy. The primary objective of the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) was to investigate whether treatment with rosuvastatin, 20 mg daily, as compared with placebo, would decrease the rate of first major cardiovascular events.
As described in detail elsewhere,17,18 men 50 years of age or older and women 60 years of age or older were eligible for the trial if they did not have a history of cardiovascular disease and if, at the initial screening visit, they had an LDL cholesterol level of less than 130 mg per deciliter (3.4 mmol per liter) and a high-sensitivity C-reactive protein level of 2.0 mg per liter or more. Other requirements for inclusion were a willingness to participate for the duration of the trial, provision of written informed consent, and a triglyceride level of less than 500 mg per deciliter (5.6 mmol per liter).
Between February 4, 2003, and December 15, 2006, a total of 89,890 people were screened for enrollment. Of these, 72,088 were ineligible, including 37,611 (52.2%) with LDL cholesterol levels of 130 mg per deciliter or more and an additional 25,993 (36.1%) with high-sensitivity C-reactive protein levels of less than 2.0 mg per liter. Other reasons for exclusion are presented in Fig. 1 in the Supplementary Appendix. A total of 17,802 people were randomly assigned to a study group.
Potential limitations of our study merit consideration.
First, we did not include people with low levels of high-sensitivity C-reactive protein in our trial,since our hypothesis-generating analysis of high-sensitivity C-reactive protein in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)12 showed extremely low event rates and no evidence that statin therapy lowered vascular risk among persons who had neither hyperlipidemia nor elevated high-sensitivity C-reactive protein levels. Thus, a trial of statin therapy involving people with both low cholesterol and low high-sensitivity C-reactive protein levels would have been not only infeasible in terms of statistical power and sample size but also highly unlikely to show a benefit.
inflammatory processes occurring in the body. This increment is due to a rise in the plasma concentration of IL-6, which is produced predominantly by macrophages as well as adipocytes. Interleukin-6 (IL-6) is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine.
CRP binds to phosphocholine on microbes. It is thought to assist in complement binding to foreign and damaged cells and enhances phagocytosis by macrophages, which express a receptor for CRP. It is also believed to play an important role in innate immunity, as an early defense system against infections.