C-reactive protein concentration and the vascular benefits of statin therapy

reposted from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62174-5/abstract

crabsallover highlights, key points, comments / links.

The Lancet, Volume 377, Issue 9764, Pages 469 - 476, 5 February 2011

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doi:10.1016/S0140-6736(10)62174-5Cite or Link Using DOI

Published Online: 28 January 2011

C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20 536 patients in the Heart Protection Study

Heart Protection Study Collaborative Group ‡

Summary

Background

It has been suggested that inflammation status, as assessed by C-reactive protein (CRP) concentration, modifies the vascular protective effects of statin therapy. In particular, there have been claims that statins might be more beneficial in people with raised CRP concentrations, and might even be ineffective in people with low concentrations of both CRP and LDL cholesterol. This study aimed to test this hypothesis.

Methods

In 69 UK hospitals, 20 536 men and women aged 40—80 years at high risk of vascular events were randomly assigned to simvastatin 40 mg daily versus matching placebo for a mean of 5·0 years. Patients were categorised into six baseline CRP groups (<1·25, 1·25—1·99, 2·00—2·99, 3·00—4·99, 5·00—7·99, and ≥8·00 mg/L). The primary endpoint for subgroup analyses was major vascular events, defined as the composite of coronary death, myocardial infarction, stroke, or revascularisation. Analysis was by intention to treat. This study is registered, number ISRCTN48489393.

Findings

Overall, allocation to simvastatin resulted in a significant 24% (95% CI 19—28) proportional reduction in the incidence of first major vascular event after randomisation (2033 [19·8%] allocated simvastatin vs 2585 [25·2%] allocated placebo). There was no evidence that the proportional reduction in this endpoint, or its components, varied with baseline CRP concentration (trend p=0·41). Even in participants with baseline CRP concentration less than 1·25 mg/L, major vascular events were significantly reduced by 29% (99% CI 12—43, p<0·0001; 239 [14·1%] vs 329 [19·4%]). No significant heterogeneity in the relative risk reduction was recorded between the four subgroups defined by the combination of low or high baseline concentrations of LDL cholesterol and CRP (p=0·72). In particular, there was clear evidence of benefit in those with both low LDL cholesterol and low CRP (27% reduction, 99% CI 11—40, p<0·0001; 295 [15·6%] vs 400 [20·9%]).

Interpretation

Evidence from this large-scale randomised trial does not lend support to the hypothesis that baseline CRP concentration modifies the vascular benefits of statin therapy materially.

Introduction

Inflammation is thought to contribute to the pathogenesis of coronary heart disease.1 C-reactive protein (CRP), an acute phase reactant synthesised by the liver, is the most extensively studied systemic marker of inflammation. Results from a meta-analysis2 of individual participant data from 54 prospective observational studies showed that CRP concentration was associated with the risk of coronary heart disease, ischaemic stroke, and vascular and non-vascular mortality. However, associations with ischaemic vascular diseases were explained largely by conventional risk factors (eg, CRP is positively correlated with smoking, diabetes, physical inactivity, blood pressure, body-mass index, non-HDL cholesterol, and triglycerides2), and so they might not reflect causality (which is supported by genetic-epidemiological studies3). Nonetheless, the ability of CRP to predict vascular risk means that it might still be useful as a biomarker to identify individuals who would particularly benefit from therapies to reduce risk.4

Some,5, 6 but not all,7 subgroup analyses undertaken in previous randomised trials of statin therapy have suggested that the vascular benefits might be greater in the presence of inflammation than in its absence. It has even been suggested that people who have low concentrations of both LDL cholesterol and CRP might not benefit much from statin therapy.8 The JUPITER trial9randomly allocated 17 802 apparently healthy men and women with LDL cholesterol concentrations less than 130 mg/L (3·4 mmol/L) but CRP concentrations 2·0 mg/L or greater to receive either rosuvastatin 20 mg daily or matching placebo. Allocation to rosuvastatin reduced LDL cholesterol at 1 year by about 50% (ie, 1·2 mmol/L) and CRP by about 40% (1·3 mg/L) and, during median treatment duration of about 2 years, there was a significant 44% reduction in the primary composite endpoint of myocardial infarction, stroke, arterial revascularisation, admission to hospital for unstable angina, or death from cardiovascular causes.9 It has been suggested that this large relative risk reduction is greater than might have been expected given the achieved LDL cholesterol reduction,9, 10 raising the possibility that the benefits of statins might be proportionally greater in people with high CRP concentrations. Secondary analyses of the JUPITER trial did not record any evidence that the effect of rosuvastatin on vascular events differed according to baseline CRP concentration,11 but these analyses included only three baseline groups for CRP (because of the relatively small number of events) and were not able to assess the effect in people with CRP concentration less than 2·0 mg/L (because they were not eligible for the trial).

The Heart Protection Study (HPS) is, to date, the largest randomised trial of statin therapy and was undertaken in high-risk patients in whom large numbers of major vascular events occurred during the study treatment period. This study tested the hypothesis that the effects of statin therapy differ according to baseline concentrations of CRP and LDL cholesterol.

The end of our National Health Service

reposted from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60110-4/fulltext?rss=yes

crabsallover highlights, key points, comments / links.

The Lancet

There is a crisis in the National Health Service (NHS). The publication of the Health and Social Care Bill last week heralds dramatic changes for the NHS, which will affect the way public health and social care are provided in the UK. Those changes alone will have huge impact, but it is the formation of an NHS Commissioning Board, and commissioning consortia, that will once and for all remove the word “national” from the health service in England. The result, due to come into force in 2013, will be the catastrophic break up of the NHS.

Maintaining the status quo in the NHS is not an option. The NHS is not delivering the care that patients need. Patients with cancer, for example, are less likely to survive in the UK than in Australia, Canada, Sweden, or Norway. Michel Coleman and colleagues' Lancet Article, published last month, reports that the survival of patients with primary colorectal, lung, breast, or ovarian cancer is lower in the UK than in other countries with similar wealth, universal access to health care, and good cancer registration data. Survival is, they argue, “the key index of the overall effectiveness of health services in the management of patients with cancer”.

Despite the huge sums of money pumped into the NHS over the past few years—particularly into the salary budget for staff—translation into benefits for patients is hard to identify. Moreover, the unyielding mountain of bureaucracy that is integral to the NHS stifles innovation, such that it is difficult to design the services needed for local populations.

Will the changes outlined in the Health and Social Care Bill solve these problems within the NHS and improve care for patients? The truth is that we do not know. What we do know is that putting general practitioners (GPs) in charge of commissioning health services for their patients is similar, in some respects, to the fundholding experiment in the 1990s. The principle then was that GPs controlled the budgets to buy the specialist care their patients needed. Fundholding took years to implement, but evidence on short-term or long-term benefits for patients is lacking. In the current Bill, health outcomes, including prevention of premature death, will be the responsibility of the NHS Commissioning Board, which has been asked to publish a business plan and annual reports on progress. That business plan is urgently needed to allow transparent appraisal of how the Board plans to monitor patients' outcomes.

The UK coalition Government has now been in power for about 8 months. Neither the Conservatives nor the Liberal Democrats included the formation of an NHS Commissioning Board, or GPs' commissioning consortia, in their health manifestos on which the electorate voted. The speed of the introduction of the Health and Social Care Bill is surprising, especially given the absence of relevant detail in the health manifestos. The Conservatives promised, if elected, to scrap “politically motivated targets that have no clinical justification” and called themselves the “party of the NHS”—a commitment that seems particularly hollow now.

Since its establishment in July, 1948, the aim of the NHS has been to offer a comprehensive service to improve health and prevent illness, available to all in England and Wales (and then extended throughout the UK), which is largely free of charge. Health care for all, for free, has been the common ethos and philosophy throughout the NHS. On July 3, 1948, in an editorial entitled “Our Service”, The Lancet commented: “Now that everyone is entitled to full medical care, the doctor can provide that care without thinking of his own profit or his patient's loss, and can allocate his efforts more according to medical priority. The money barrier has of course protected him against people who do not really require help, but it has also separated him from people who really do.” Now, GPs will return to the market place and will decide what care they can afford to provide for their patients, and who will be the provider. The emphasis will move from clinical need (GPs' forte) back to cost (not what GPs were trained to evaluate). The ethos will become that of the individual providers, and will differ accordingly throughout England, replacing the philosophy of a genuinely national health service.

Health professionals cannot say that no change is needed—it most certainly is. But there is sufficient uncertainty and concern about the changes outlined in the Health and Social Care Bill to pause, to learn from the past, and to consider what the changes mean for patients' outcomes. As it stands, the UK Government's new Bill spells the end of the NHS.

reposted from: http://www.highlighthealth.com/cancer/daily-aspirin-may-reduce-cancer-risk/

crabsallover highlights, key points, comments / links.

 "Aspirin reduced death from gastrointestinal cancers and non-gastrointestinal solid cancers like those of the lung, prostate, bladder and kidney, but not from hematological cancers. This may be because aspirin seemed to only reduce deaths from cancers that are predominantly adenocarcinomas, meaning that they originated from epithelial cells — cells that line the cavities and organs in the body and thus form the boundary between one tissue and another. Aspirin had no effect on other, non-cancer deaths."
...
" In the future they plan to extend their analysis to beyond twenty years to look for any late rebound in cancer deaths, and to see if they can replicate their findings with alternate-day — instead of daily — aspirin."

‘Statins may have given me Motor Neurone Disease’

reposted from: http://www.bournemouthecho.co.uk/news/8823062.___Statins_may_have_given_me_MND___/

crabsallover highlights, key points, comments / links.

thanks to Sharon Street for this article.
“Statins have been very widely prescribed since the mid-1990s, which means that some recipients may develop Motor Neurone Disease for quite unrelated reasons.” Was it just coincidence that he went on Statins then got MND 4 months later? Over a 4 month period what are the chances that anyone of his age would get MND? 

‘Statins may have given me MND’

2:00pm Monday 31st January 2011

• By Joanna Codd »

A TERMINALLY ill Bournemouth man is questioning whether a commonly prescribed cholesterol-lowering drug is to blame for his motor neurone disease.

Former manager Malcolm Chapman was put on simvastatin and blood pressure tablets in December 2009 after going to his GP complaining of constant tiredness. At the time, he was three stone overweight.

Mr Chapman claims he was never told why he was being given simvastatin. His cholesterol level was not monitored and he was not warned that statins can cause muscle weakness. 

In February last year, Mr Chapman, of Boscombe, developed weakness around his knee. “My mind became confused and the muscle weakness spread to my face. I could no longer laugh or cry properly,” he recalled.

The following month, his left leg gave way under him and his voice had become slurred. His wife Susan took him to Royal Bournemouth Hospital’s emergency department, but he was sent home after a scan and a blood test.

His GP referred him to a neurologist, but while waiting for an appointment, Mr Chapman stopped taking his medication.

In July the specialist said he had compressed discs in his back, had not suffered a stroke and did not have motor neurone disease.

Mr Chapman, 62, was finally diagnosed with MND at Southampton last October and told he only had a year or two to live. Although he can still walk, his speech is hard to understand and he needs round-the-clock care from his wife and daughter Zoe.

“I want to warn people to be careful. If they don’t have heart problems, they shouldn’t go on statins, and if they do, they should be monitored,” he said.

In 2007, a World Health Organisation’s international drug monitoring centre called for further research after an unusually high rate of MND-type symptoms in people on statins. (Reference?)

But a spokesperson for NHS Bournemouth and Poole said: “According to the authoritative NHS Evidence source, Motor Neurone Disease is not an identified side-effect of statins.

“A system exists by which GPs are encouraged to report adverse drug reactions so the likelihood of such a link would become obvious very quickly.

“Statins have been very widely prescribed since the mid-1990s, which means that some recipients may develop Motor Neurone Disease for quite unrelated reasons.”

Statins—should we adjust the risk:benefit ratio?

reposted from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60111-6/fulltext?rss=yes

crabsallover highlights, key points, comments / links.

The Lancet

The prevailing opinion that statins are an elixir for long life was challenged with the recent publication of the Cochrane review, Statins for the primary prevention of cardiovascular disease. After analysing 16 trial arms with 34 272 participants, the authors found no evidence of harm, and mortality, composite cardiovascular endpoints, and revascularisations were reduced. But they concluded: “caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.”

The conclusion seems at odds with the findings. However, the authors found the evidence of insufficient quality to allow them to conclude differently; many trials included patients with a previous cardiovascular event, and the authors state that poor reporting of adverse events and selective reporting of outcomes contributed to their failure to draw a positive conclusion. They state that the evidence is “impossible to disentangle without individual patient data”.

The authors' conclusion is also at odds with the recent Cholesterol Treatment Trialists' (CTT) Collaboration meta-analysis, published in The Lancet. Individual patient data from around 70 000 patients with no previous cardiovascular disease were analysed, and showed that statins significantly reduced the relative risk of a cardiovascular event by 0·75 per 1 mmol fall in LDL cholesterol.

Unfortunately, the media are quick to forget, and have reported the Cochrane's headline-grabbing details with scant regard for the preceding evidence. This approach will have left many patients at best bewildered. The media have also largely ignored the Cochrane authors' conclusion that the results support guidelines from the UK's National Institute of Health and Clinical Excellence, which recommends statins are considered for primary prevention in patients with an annual incidence of cardiovascular events of over 2%.

So what should general practitioners (GPs), who are faced with increasing numbers of low-risk patients worried about mildly raised cholesterol, do? The Cochrane review has muddied the water, but the available evidence shows that statins are safe, and evidence from the CTT Collaboration also shows that reductions in cholesterol per se can produce benefits. So, the simple answer is that GPs should do what they always have done—clearly explain the risks and benefits to patients so that the patient is able to choose the strategy that is best for them.