The effect of statins on average survival in randomised trials, an analysis of end point postponement

1. Malene Lopez Kristensen, 
2. Palle Mark Christensen, 
3. Jesper Hallas
5. Objective To estimate the average postponement of death in statin trials.
6. Primary outcome measures The average postponement of death as represented by the area between the survival curves.
   Results 6 studies for primary prevention and 5 for secondary prevention with a follow-up between 2.0 and 6.1 years were identified. Death was postponed between −5 and 19 days in primary prevention trials and between −10 and 27 days in secondary prevention trials. The median postponement of death for primary and secondary prevention trials were 3.2 and 4.1 days, respectively.
7. Conclusions Statin treatment results in a surprisingly small average gain in overall survival within the trials’ running time. For patients whose life expectancy is limited or who have adverse effects of treatment, withholding statin therapy should be considered.

Strengths and limitations of this study

• This is the first study ever to systematically evaluate statin trials using average postponement of death as the primary outcome.
• We have only estimated the survival gain achieved within the trials’ running time, whereas in real life, treatment is often continued much longer.
• We have only focused on all-cause mortality. Other outcomes may also be relevant, for example, non-fatal cardiovascular end points.

Read the complete article here.

The Lancet published a meta-analysis of 27 statin trials

Data, Drugs, and Deception: a True Story

 

Wednesday, May 23, 2012

      

Last week The Lancet published a meta-analysis of 27 statin trials, an attempt to determine whether patients with no history of heart problems benefit from the drugs—true story. The topic is controversial, and no less than six conflicting meta-analyses have been performed—also a true story. But last week’s study claims to show, once and for all, that for these very low risk patients, statins save lives—true story.

Actual true story: the conclusions of this study are neither novel nor valid.

The Lancet meta-analysis, authored by the Cholesterol Treatment Trialists group, examines individual patient data from 27 statin studies. Their findings disagree with an analysis published in 2010 in the Archives of Internal Medicine, and with analyses from two equally respected publications, the Therapeutics Letter and the Cochrane Collaboration.* Despite this history of dueling data the authors of last week’s meta-analysis, in a remarkable break from scientific decorum, conclude their report with a directive for the writers of statin guidelines: the drugs should be broadly recommended based on the new analysis.

As an editorialist points out, if implemented, the CTT group recommendations in the United States would lead to 64 million people, more than half of the population over the age of 35, being started on statin therapy—true story.

Where is the magic, you ask, in this latest effort? What is different? In some ways, nothing. Indeed just a year and a half earlier The Lancet published a meta-analysis of 26 of the same 27 studies, with the same results, by the same authors (true story, and an odd choice on the part of the journal). So the findings aren’t new. They are, however, at odds with other meta-analyses. Why? It is the way they calculated their numbers. This meta-analysis, like the earlier one from the same group, reports outcomes per-cholesterol-reduction. The unit they use is a “1 mmol/L reduction in low density lipoprotein (LDL)”, in common U.S. terms, a roughly 40-point drop in LDL.

That’s the magic: each of the benefits reported in the paper refers to patients with a 40-point cholesterol drop. Voilá. One can immediately see why these numbers would look different than numbers from reviews that asked a more basic question: did people who took statins die less often than people taking a placebo? (The only important question.) Instead, they shifted the data so that their numbers corresponded precisely to patients whose cholesterol responded perfectly.
Patients whose cholesterol drops 40 points are different than others, and not just because their body had an ideal response to the drug. They may also be taking the drug more regularly, and more motivated. Or they may be exercising more, or eating right, and more health conscious than other patients. So it should be no surprise that this analysis comes up with different numbers than a simple comparison of statins versus placebo pills. Ultimately, then, this new information tells us little or nothing about the benefits someone might expect if they take a statin. Instead it tells us the average benefits among those who had a 40-point drop in LDL.

But LDL drop cannot be predicted. Some won’t drop at all, some will drop just a bit, and some may drop more. Therefore the numbers here tell an interesting story about certain patients who took statins, but they have no relevance to patients and doctors considering statins. And yet, the latter group is the target of the study's concusions.

True story: in prior meta-analyses that found no mortality benefit the investigators simply looked at studies of patients without heart disease and compared mortality between the statin groups and the placebo groups. No machinations, no acrobatics, no per-unit-cholesterol. They took a Joe Friday approach (just the facts, ma’am), and found no mortality benefit.

Perhaps never has a statistical deception been so cleverly buried, in plain sight. The study answers this question: how much did the people who responded well to the drug benefit? This is, by definition, a circular and retrospective question: revisiting old data and re-tailoring the question to arrive at a conclusion. And to be fair they may have answered an interesting, and in some ways contributory, question. However the authors’ conclusions imply that they answered a different, much bigger question. And that is not a true story.

Guideline writers, doctors, patients, journalists, and policy makers will all have to pay close attention to avoid the trappings of deceptive data, dressed up as a true story.

*The Cochrane Collaboration analysis reports an overall mortality benefit with statins (RR=0.86), however their summary suggests that statins should be used for primary prevention “with caution.” In particular on p.12, after a discussion of the biases in many of the trials that led to their numerical finding, they clearly state that using statins for patients with anything less than a 2% per year risk of coronary events “is not supported by existing evidence.” This cutoff encompasses virtually all people that would be considered candidates for primary prevention.
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Read the complete article here.

Dietary Iron Intake & Body Iron Stores Are Associated with Coronary Heart Disease

Dietary Iron Intake and Body Iron Stores Are Associated with Risk of Coronary Heart Disease

Abstract

The link between iron intake as well as body iron stores and coronary heart disease (CHD) has been contentiously debated, and the epidemiologic evidence is inconsistent. We aimed to quantitatively summarize the literature on the association between dietary iron intake/body iron stores and CHD risk by conducting a meta-analysis of prospective cohort studies. PubMed was used to find studies published through June 2013 in peer-reviewed journals. Embase or a hand search of relevant articles was used to obtain additional articles. The pooled RRs of CHD incidence and mortality with 95% CIs were calculated by using either a random-effects or fixed-effects model, as appropriate. Twenty-one eligible studies (32 cohorts) including 292,454 participants with an average of 10.2 y of follow-up were included. Heme iron was found to be positively associated with CHD incidence (RR: 1.57; 95% CI: 1.28, 1.94), whereas total iron was inversely associated (RR: 0.85; 95% CI: 0.73, 0.999). Neither heme-iron nor total iron intakes were significantly associated with CHD mortality. Both transferrin saturation and serum iron were inversely related to CHD incidence [RR (95% CI): 0.76 (0.66, 0.88) and 0.68 (0.56, 0.82), respectively], but only transferrin saturation was inversely associated with CHD mortality (RR: 0.85; 95% CI: 0.73, 0.99). In conclusion, total iron intake and serum iron concentrations were inversely associated with CHD incidence, but heme iron intake was positively related to CHD incidence. Elevated serum transferrin saturation concentration was inversely associated with both CHD incidence and mortality. Future research is needed to establish the causal relation and to elucidate potential mechanisms.

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Read the complete article here.

My 'take away' points from this abstract:
1. The link between iron intake as well as body iron stores and coronary heart disease (CHD) has been contentiously debated.
2. the epidemiologic evidence is inconsistent
3. Heme iron was found to be positively associated with CHD incidence
4. total iron was inversely associated with CHD incidence
5. Neither heme-iron nor total iron intakes were significantly associated with CHD mortality
6. Both transferrin saturation and serum iron were inversely related to CHD incidence
7. heme iron intake was positively related to CHD incidence and mortality.
8. Elevated serum transferrin saturation concentration was inversely associated with both CHD incidence and mortality

Another large study is linking statin use to the development of cataracts - Wood

Statins linked to cataracts in large, retrospective study

September 19, 2013 Shelley Wood

            

 

 

 

 

 

 

 

 

 

 

 

San Antonio, TX - Another large study is linking statin use to the development of cataracts [1]. The latest, following on a Canadian analysis last year, is a propensity score-matched analysis of over 45 000 subjects in a military healthcare system, published this week in JAMA Ophthalmology.

 

As Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center, San Antonio, TX) and colleagues point out, observational studies of statins have been conflicting, with some suggesting an increased risk of cataracts with statin use while others appear to show a beneficial effect of statins on cataract risk. At the recent European Society of Cardiology (ESC) 2013 Congress, Dr John B Kostis (Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ) presented the results of a random-effects meta-analysis, showing a 20% lower rate of cataracts with statin use compared with no statin use, with a more pronounced benefit seen when statins were started in younger patients. 

 

The meta-analysis published today, however, found the opposite. It matched 6972 statin users with nonusers within the San Antonio Military Multi-Market Area health system using propensity scores based on variables that increased the likelihood of receiving statins and increased the risk of developing cataracts. Statin users had to have been on the drugs for more than 90 days; simvastatin was prescribed in almost three-quarters of the patients.

 

They found that statin users in the propensity-matched analysis had a 9% increase in cataracts. In secondary analyses that looked at all patients with no comorbidities (based on the Charlson index) at baseline, the risk of developing cataracts was 29% higher in the statin users. Results were consistent regardless of whether patients had been taking statins for two, four, or six years, authors note.

 

The study is the first to use propensity matching to try to eliminate baseline confounding—making it a key contribution to the relatively recent research into this potential interaction. To heartwire, senior author Dr Ishak Mansi (VA North Texas Health Care System, Dallas) noted that there are a number of ways in which statins could be a marker for important confounders, including accessible healthcare and health insurance, as well as underlying risk factors such as smoking, diabetes, and older age—all of which are also risk factors for cataract.

 

That kind of confounding may have been a factor in the Kostis et al meta-analysis at ESC, Mansi commented, when asked about the divergent findings, adding that since the paper is not yet published, he hasn't had a chance to review its methodology.

 

"Without knowing the specifics of the paper . . . I can generally say the following: During the mid-1990s and early 2000s, there were many papers that associated statin use with improved outcomes of many diseases such as cataract, fracture, infection, dementia, etc; however, recently, it was realized that statin use was associated with 'healthy-user bias.' That is to say, individuals who are health-conscious are more likely to take statins, and better outcomes may be secondary for their health consciousness and not due to the statin itself. . . . Therefore, if this meta-analysis included large-volume studies that date back to this period of time, their results may be affected by these biases of these studies."

 

Cardiologists have had plenty of experience with seemingly contradictory studies, he added. "Historically, we have been through these controversies on several topics, such as the use of hormonal-replacement therapy, treatment of chronic systolic heart failures with antiarrhythmic drugs, etc. We will have to study and search for our best capabilities until we reach an answer."

 

"Statins are very effective medications; therefore, side effects are expected. Healthcare providers should make sure that there is justifiable indication to prescribe statins according to guidelines and that the potential benefits outweigh the potential risks of side effects for individual patients. These medications should not be prescribed lightly."

 

For the public, however, the message is slightly different. "For some patients, these medications have been a main tool in treatment of heart disease and should not be stopped because of a small higher risk of association with other diseases," Mansi said. All effective medications can be expected to have side effects, he continued. "It is much better to do your best to lower your own risk of cardiovascular disease (if feasible) by stopping smoking and keeping physically active than to take a pill to lower your risk of heart disease."

 

Source

1. Leuschen J, Mortensen EM, Frel CR, et al. JAMA Ophthalmol 2013; DOI:10.1001/.jamainternmed.2013.4575. Available at: http://archopht.jamanetwork.com/journal.aspx.

Related links

• Statins linked with development of cataracts
  [Lipid/Metabolic > Lipid/Metabolic; Aug 13, 2012]
• Genetic marker may identify risk for statin-induced myopathy
  [Clinical Conditions > Lipid/Metabolic; Sep 06, 2013]
• Treat risk and not LDL-cholesterol targets, new perspective argues
  [Lipid/Metabolic > Lipid/Metabolic; Jan 19, 2012]

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Read the complete article here.http://www.theheart.org/article/1584825.do

 

The American Heart Association misrepresented data on saturated v. polyunsaturated fats

The American Heart Association misrepresented data on saturated v. polyunsaturated fats: According to the paper... http://fb.me/CDBem1kd

Thank You Weston A Price for this information!
========================================================
Some Quotes:

"Peer review is critical for ensuring that evidence assembled in a meta-analysis is complete and impartial. Regrettably, the recent AHA Advisory [1] relied heavily upon a one-line meta-analysis cited in a non peer-reviewed book chapter [2] to support its position that high intakes of omega-6 fatty acids reduce CHD. Unfortunately, the credibility of this advisory is undermined by four additional critical errors."

1) The AHA Advisory mistakenly cited the Sydney Diet-Heart Study...

2) Although the AHA Advisory [1] criticizes other studies for failing to distinguish between “distinct effects” of omega-3 and omega-6 fatty acids, it commits this error throughout.

3) The AHA Advisory imprecisely contends that its analysis pertains to trials that “evaluated the effects of replacing saturated fatty acids with PUFAs” [1] despite its citation of trials where experimental diets displaced large quantities of trans fatty acid-rich partially hydrogenated oils.

4) The AHA Advisory failed to indicate that the Rose Corn Oil Trial [5] gives a rare opportunity to evaluate the specific effects of increased LA, because corn oil has little omega-3 ALA.

 

 

The advisory fails to inform the public that an important tissue indicator of CVD risk the ‘Omega-3 Index’5, reflects the proportion of EPA and DHA in erythrocytes, a representative phospholipid eicosanoid precursor pool. The Omega-3 Index is regarded5 as superior to LDL as a biomarker predicting cardiovascular mortality. Paradoxically, the advisory reports that increasing LA intakes decreases EPA accretion, (i.e. lowers the Omega-3 Index and increases CVD risk), but implies without comparative quantitation that lowering LA intakes would elevate LDL levels and increase net CVD risk. However, lowering LA by LNA substitution could maintain PUFA intakes and result in a more favorable Omega-3 Index.

The advisory unfortunately moves from suggestive and highly conditional interpretations to the

unsupported clinical admonition that “To reduce omega-6 PUFA intakes from their current levels would be more likely to increase than to decrease risk for CHD.”
==================================================================
Please read the complete paper here.



 

Do statins really reduce the risk of cancer? - Briffa

Do statins really reduce the risk of cancer?

Nov, Fri 9th, 2012 By : Dr John Briffa

 

Yesterday saw the on-line publication of a study in the New England Journal of Medicine (NEJM) that concerns statins and is getting more than its fair share of media attention. The study, conducted in Denmark, analysed the rates of death from cancer in individuals taking statins, and compared them to those in individuals not taking these drugs. Those taking statins were found to be at a statistically significant reduced risk of dying from cancer. Some seem keen to claim that statins may not only be an answer to heart disease, but our cancer woes too. Take this headline for example which you can find here: ‘Statins cut mortality in cancer patients’. The wording of this title on a website dedicated to the education of doctors strongly suggests that statins actually reduce the risk of death from cancer.

But, not so fast. The NEJM study is what is known as ‘epidemiological’ or ‘observational’ study. The study tells us that statin use is associated with a reduced risk of death from cancer, but it can’t tell us whether or not statins actually cut cancer risk.

One fundamental problem with studies of this nature is that they are subject to what is known as the ‘healthy user effect’. Basically, what this means is that healthier, often more health-conscious individuals are more likely to end up on statins than less healthy, not so health-conscious individuals. Because of this, it’s possible that the apparent benefits of statins with regard to cancer (or anything else) are not to do with the drugs themselves, but the health characteristics of those more likely to take statins.

If we really want to know if statins reduce the risk of cancer death then we need to look to what are known as ‘intervention studies’ in which, usually, roughly equivalent groups of individuals are given statins or placebo. These studies, the gold standard of which are ‘randomised controlled trials’ do have the potential of discerning the true effects of drugs and other treatments.

Single studies such as these can provide useful data, but sometimes it makes sense to amass data from several studies to get a decent overview of the impact of a drug or class of drugs. Such grouping of studies together are referred to as ‘meta-analyses’.

One meta-analysis published in 2009 found that statin use was not associated with a reduced risk of cancer [2]. A more recent meta-analysis published this year found the same thing [3]. Meta-analyses of intervention studies are not perfect, but they are much better than (crappy) single epidemiological studies like the one currently doing the rounds. And it’s perhaps worth bearing in mind that there as been at least some concern about the impact statins might have on cancer risk in the elderly. In one study, statin use (compared to placebo) increased the risk of cancer by 25 per cent (statistically significant) [4].

Put in this context, the frothing enthusiasm exhibited by some regarding this latest study seems inappropriate. And for a website dedicated to the education of doctors to proclaim that ‘Statins cut mortality in cancer patients’ is downright negligent.

References:
1. Nielsen SF, et al. Statin Use and Reduced Cancer-Related Mortality. NEJM published online 8 October 2012
2. Brugts JJ, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009;338:b2376.
3. Cholesterol treatment trialists’ collaboraton. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One 2012;7(1):e29849. Epub 2012 Jan 19.
4. Shepherd J, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360(9346):1623-30
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Read the complete article here.

Omega-3/Fish Oil.... Good Bad? - Blanchet

Omega-3/Fish Oil.... Good Bad?

Listen to my doctor discuss over interpretation of a single bad study.

Several articles in the news lately, pretty much said that taking fish oil, or omega 3's, did nothing to help prevent heart disease. Should you toss your supply? Hear what Dr. Blanchet has to say about omega 3’s and their role in our health. Find out the facts about the studies that were done which prompted the media concern.


http://tuesdaytalkshow.podomatic.com/entry/2012-10-18T14_26_49-07_00

New JAMA Study Bakes Fish Oils- Don’t Believe It! - Cohen

New JAMA Study Bakes Fish Oils- Don’t Believe It!

 

 

Dear Pharmacist,

 

I just heard about the new study that says fish oil supplements don’t prevent heart attacks, and may not help us. Should I keep taking fish oils? –S.S., Chicago

Answer: Yes, if they’re high-quality. The “study” wasn’t a study at all, it was a meta-analysis, which means researchers examine results from a bunch of trials and draw their own conclusions based on the collective data. The meta-analysis you refer to appeared in the September 2012 issue of JAMA and included 68,000 participants in 20 different studies that covered a time frame 24 years. I have some problems with their opinion that fish oils are fairly worthless. The research I know of suggests strong benefits to the heart and arteries when you take high-quality fish oils. These are my problems with the JAMA article:

1. The researchers only reviewed 20 studies, but there are thousands that suggest cardiovascular protection by fish oils, particularly the EPA and DHA components. You’re not going getting the full picture from 20 studies.
2. How much fish oil was used? Most people were taking 1,000mg per day, but you need about 2,000 mg per day (total daily dose of EPA and DHA) to truly impact coronary heart disease. We come up therapeutically short! What about the ratio of EPA to DHA; ideally, I’d like it to be 3:2; for example, 600mg of EPA to 400mg DHA is a 3:2 ratio.

3. The looked at chronically ill people who had serious conditions, like they had already suffered a heart attack and stroke, not folks taking it for prevention. Fish oils are not intended to prevent heart attack or stroke. Plus, it’s super hard to prevent more health catastrophes, once you’ve had one. Feeling skewed?

4. What about the medications these folks were taking? The participants were taking all sorts of blood pressure pills and diuretics, most of which just so happen to be drug muggers of magnesium! Do you realize that serious uncorrected magnesium deficiency can cause a heart attack, no matter how much fish oil you take! To me, this is a huge gap in their premature conclusion.
5. What about Gamma Linolenic Acid or “GLA” status? When you take fish oils, an omega 3 fatty acid, you have to also supplement with GLA (an omega 6 fatty acid) because high doses of fish oils will cause drug mugging of GLA. For example, if you take 1,000 mg of fish oil (EPA and DHA totaled together), you need 500mg GLA at the same time. Evening primrose oil supplements can provide this GLA. This is important because GLA deficiency can increase your tendency to form clots (bad). GLA is known to protect the heart, without adequate amounts, you could suffer cardiac consequences, and this was not even addressed.

Even the American Heart Association approves of fish oils for heart health. Think smart and don’t be fooled by a single study intended to sway you away from decades of positive research.
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READ THE COMPLETE ARTICLE HERE.
Also watch Suzy's video discussing this here.

Statins for healthy people? Hang on a minute…

Statins for healthy people? Hang on a minute…

I’ve had a few emails today alerting me to reports of a study concerning the use of statins in healthy individuals. The study in question is a meta-analysis (grouping together of similar studies) of statin trials [1]. Part of this meta-analysis involved assessing the impact of statin therapy in individuals deemed to be at relatively low risk of cardiovascular events such as heart attacks and strokes. One of the stand-out findings of this study is that statins led to a statistically significant reduction in risk of ‘major vascular events’. This was even true for individuals at less than 10 per cent risk of vascular events over a 5-year period. This has led to the suggestion that statins used might be widened to even people at low risk of cardiovascular problems.

Before we swallow this idea, though, it is perhaps a good idea to see just how effective statins were found to be in this meta-analsysis. First of all, what is meant by ‘major vascular events’? Actually, this is a term that includes many different potential outcomes including fatal and non-fatal heart attacks and strokes and ‘revascularisation’ procedures (such as placing tubes called stents in the coronary arteries). When a lot of different outcomes are grouped together, it makes it much more likely that a ‘statistically significant’ results will emerge.

When the outcomes are narrowed a little, the results are less impressive. For example, when we look at risk of death from any vascular event (a heart attack or stroke), we find that statins did not reduce risk in individuals deemed to be at low risk (<10 per cent over 5 years). This, by the way, was even true for those who had known vascular disease.

The ‘positive’ findings from this study have, as is often the case, been expressed as reductions in relative risk. The risk of vascular events overall was 21 per cent lower for each 1 mmol/l (39 mg/ml) reduction in levels of low density lipoprotein cholesterol (LDL-C). However, when overall risk is low, then a relative risk reduction might not amount to much in real terms.

We’re told by the authors this meta-analysis that treating with statins prevented 11 major vascular events for every 1000 people treated for a period of 5 years. Put another way, 91 people would need to be treated for 5 years to prevent one major vascular event. Or in other words, only about 1 per cent of people treated with statins for 5 years will benefit (and about 99 per cent won’t).

Overall, lowering LDL-C by 1 mmol/l was found to reduce the risk of death by 9 per cent over a 5-year period. Again, this might sound like a positive finding to some, but the actual reduction in risk of death was 0.2 per cent per year. What this means is that at this level of cholesterol reduction, 500 individuals would need to be treated with statins for a year for one person to have his/her life saved.
The authors of this meta-analysis give us some soothing reassurances about the fact that the benefits of statins vastly outweighing the risks of adverse events such as myopapthy (muscle pain and weakness). They quote of the excess incidence of myopathy as 0.5 cases per 1000 people over 5 years. However, the source they quote is based on diagnosing myopathy once the marker for muscle damage (creatine kinase) is at least TEN TIMES the upper limit of normal. Many individuals will have significant pain and weakness with much lower levels of creatine kinase. Statins are also linked with adverse effects on the liver and kidneys, and increase risk of diabetes too.

Despite the very positive interpretation of the data by the study authors and the media, this meta-analysis shows us again what previous evidence has revealed: statins are highly ineffective in terms of improving health and saving lives. And their risks are generally downplayed.

Collectively, the authors of the meta-analysis are referred to as the Cholesterol Treatment Trialists’ (CTT) Collaborators, including researchers from Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University. The conflicts of interest statement which accompanies this paper informs us that: “Some members of the writing committee have received reimbursement of costs to participate in scientific meetings from the pharmaceutical industry.” I suppose this may account, at least in part, for a data interpretation that appears so heavily biased towards statins.

References:
Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta
-analysis of individual data from 27 randomised trials. The Lancet epub 17th May 2012
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Read the full atricle here.http://www.drbriffa.com/2012/05/18/statins-for-healthy-people-hang-on-a-minute/

So what’s wrong with low-carbohydrate diets?

Dr. John Bariffa just posted an article on his blog titled What’s wrong with the dietary advice Diabetes UK dishes out to diabetics? Now this blog (Credible Evidence) is not ususlly about diabetes, rather (you guessed it - this blog is primarily about heart disease) but there is a strong connection between the two diseases.

I have reproduced part of Dr. Briffa's article because he makes several strong statements regarding heart disease and I thought it appropriate to post them here. I encourage you to follow the link to his site to read the full article and to check out the references he provided.

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"            So what’s wrong with low-carbohydrate diets?
The usual accusation that such diets are high in fat, including ‘saturated’ fat that can cause heart disease (that diabetics are prone to). Actually, there is good evidence that when carbohydrate is cut from the diet, while the percentage of fat increases in the diet, the absolute amount of fat in the diet stays about the same (in other words, those switching to low-carb eating don’t generally eat more fat as a result).

This issue is a moot point, because there really is no evidence that saturated fat causes heart disease anyway. There have been several recent major reviews of the evidence regarding role that saturated fat, or fat in general, has in heart disease.

One such review conducted by researchers from McMaster University in Canada found that epidemiological evidence simply does not support a link between saturated fat and heart disease. Another recent study out of Oakland Research Institute in California, USA – this one, a meta-analysis (adding together of several similar studies) found saturated fat consumption has no links with heart disease risk.

Yet another comprehensive review of the relevant literature was performed as part of an ‘Expert Consultation’ held jointly by the World Health Organization (WHO) and Food and Agriculture Organization (FAO) of the US. Again, no association was found between saturated fat and heart disease. This review also included a meta-analysis of intervention studies in which the effects of low-fat diets (these usually target saturated fat specifically) were assessed. Lower fat diets were not found to reduce the risk of either heart attack or risk of death due to heart disease.

The most recent review of the evidence was a 2011 meta-analysis, in which the results of 48 studies were pooled together. Each of these studies tested the effect of reducing fat and/or modifying its nature in the diet. In general, the study subjects reduced saturated fat intake and/or replaced it at least partially with so-called ‘polyunsaturated’ fats (e.g. vegetable oils). The results of this review showed that these interventions did nothing to reduce the risk death due to cardiovascular disease nor overall risk of death. In studies in which lowering and/or modification of fat was the only intervention, risk of cardiovascular events such as heart disease and stroke was not reduced either."
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Read the complete article by Dr John Bariffa here.

Scientists sometimes shift the scientific goalposts

Dr. John Briffa

Scientists sometimes shift the scientific goalposts

Posted on 10 August 2011

It’s easy to believe that statins have dramatic life-saving properties. The reality is, however, that for the majority of people who take them, they don’t. In the biggest and best review published to date, statins were not found to reduce overall risk of death in individuals with no previous history of cardiovascular disease [1]. What this study shows is that for great majority of people who take statins, the chances of them saving their life are, essentially, nil (just so you know).

Of course, you wouldn’t expect everyone to take this finding lying down. A number of people responded to this study with letters to the journal in which it appeared, attempting to cast doubt on its findings. None of it amounted to much, but I thought I would focus on one response, which in my view demonstrates how some scientists and doctors attempt to shift the scientific goalposts to make their point and suit their ends.

The response came from Drs Gabriel Chodick and Varda Shalev [2]. The main thrust of their objections come in the form of three studies that were included in the review referred to above that they claim have ‘major limitations’. Here’s what they say about each of these studies:

“…their meta-analysis included 3 studies with major limitations: a significant decrement in low-density lipoprotein cholesterol levels over the study period in the placebo arm (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]), old age at therapy initiation (Pravastatin in Elderly Individuals at Risk of Vascular Disease [PROSPER] Study), and incomplete information on low-density lipoprotein cholesterol levels over the follow-up period (Air Force/Texas Coronary Atherosclerosis Prevention Study [AFCAPS/TexCAPS]). All these studies showed negative results; their inclusion would have biased against finding a benefit to statin treatment.”

With regard to the first study, what Drs Chodick and Shalev seem to be saying is that the control group (the group treated with placebo rather than statin) saw natural reductions in cholesterol, so the benefits of taking a statin did not to show up. However, the impact that statins had on cholesterol levels relative to a control group is not important – the only important thing is the impact statins had on health (and, in particular, overall risk of death). This is also true for the last study highlighted by Drs Chodick and Shalev.

As regard the second study, it’s not clear why the advanced years of participants would be a barrier to determining the effectiveness of statins. Actually, the elderly are known to be at particularly high risk of cardiovascular disease, meaning that if anything, this population would, theoretically, be generally most likely to benefit from statin therapy.

In summary: none of Drs Chodick and Shalev’s objections hold any water at all. But they don’t stop there. Here’s the final paragraph from their letter.

“Also, randomized controlled trials are often characterized by limited follow-up periods. Therefore, all-cause mortality benefits may not be apparent in randomized controlled trials among a primary prevention population. It would be informative in this regard to take into account the results of large observational studies with longer follow-up periods to better capture the benefits of statins in primary prevention patients.”

What they’re saying here is that clinical trials don’t go on long enough to detect benefits. It’s better, in their mind, to revert to longer studies that are observational (also known as ‘epidemiological’) in nature. However, such studies look at associations between things, but can never be used to prove the benefits of statins. Only intervention studies can do this.

So, what the authors of this letter are effectively saying is that we should ignore the best evidence we have in favour of quite-useless epidemiological evidence.

One of the authors of this letter is, in fact, an epidemiologist, and really should know better. But then again, both of the authors work for a company that assists drug companies in, among other things, ‘reducing the time to market’ and the writing and submission of scientific articles for publication.

See here for more details. It’s a clear conflict of interest, of course, and perhaps goes some way to explain why they make apparently spurious objections to existing evidence and appear to be calling for an approach that can never really get to the truth.

References:
1. Ray KK, et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65 229 participants. Arch Intern Med. 2010;170(12):1024-1031
2. Chodick G, et al. Statins and all-cause mortality in high-risk primary prevention: a second look at the results. Arch Intern Med. 2010;170(22):2041-2
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Read the full article here.

Dr. Briffa on statins and cholesterol reduction

Recent review on statins ignores body of evidence that suggests these drugs don’t work through cholesterol-reduction



http://www.drbriffa.com/blog/   November 15, 2010

Recent review on statins ignores body of evidence that suggests these drugs don’t work through cholesterol-reduction

Big cholesterol news emerged last week on the publication (much publicised) of a massive meta-analysis of statin treatment in those at relatively high risk of cardiovascular disease. The idea of this meta-analysis was to assess whether aggressive lowering of cholesterol (specifically LDL-cholesterol) brings additional benefits in terms of cardiovascular disease protection. The meta-analysis included results from a total of 26 trials (involving a total of about 170,000 individuals) [1].

What this meta-analysis found was that more intensive lowering of cholesterol was associated with a reduced risk of ‘vascular events’ such as heart attacks, fatal heart attacks and the most common form of stroke (ischaemic stroke). The authors state that for each 1.0 mmol/L (39 mg/dl) reduction in LDL-cholesterol, risk of vascular events was reduced by about a fifth. They go on to say “reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50 per cent.”

Perhaps not surprisingly, this meta-analysis is being used to ram home the conventional view that cholesterol causes cardiovascular disease, and that lower levels of LDL-cholesterol are better. However, there are a number of reasons why this study fails to tell the whole story about statins and cholesterol reduction.

Statin drugs have a number of different mechanisms which might allow them to reduce cardiovascular disease risk in a way which has nothing to do with cholesterol reduction. For example, statins have anti-inflammatory effects, which we would expect to lead to reduced risk of cardiovascular disease. Now, when we intensively lower cholesterol with these drugs, non-cholesterol-related effects (e.g. anti-inflammatory action) will generally be increased too. So, we cannot assume that any additional benefits from more intensive statin therapy have come from more intensive lowering of cholesterol.

In this meta-analysis, the results of a large number of studies was pooled. The problem is, these studies used a range of different drugs at different doses. Sometimes, the drugs were being tested against placebos, and sometimes they were being tested against other drugs. Rarely, two doses of the same drug were tested. Basically, the studies represent a huge hotchpotch of ‘methodologies’ and ‘variables’.

If you really want to take a scientific approach to assessing the role of cholesterol reduction on health, you would ‘control your variables’. This basically means changing only one thing. So, for instance, you could give two groups of people differing doses of the same statin. You could then see if the group on the higher dose had additional benefits, and also see if this appeared to be related to cholesterol reduction or something else. You’d be surprised how rarely such studies are done.

One example of such a study is the so-called TNT study [2]. Here, individuals with heart disease (very high risk of future vascular events) were given either 10 or 80 mg of atorvastatin for an average of about 5 years. The higher dose did lead to lower LDL levels and lower risk of death due to heart-related disease. The absolute reduce in risk was 0.5 per cent, by the way, so nothing to get too excited about. Plus, this study did not report on the non-cholesterol-related effects of the two different dosages, and so it’s impossible to gauge if the relative benefit of the higher dosage was down to LDL reduction and/or something else.

It should also be borne in mind, by the way, that the higher dose of statin in this study (eight times the lower dose, remember) did not lead to a reduction in overall risk of death. In other words, taking 8 times the dose of this drug for five years did not, overall, extend life by a single day, even in individuals at high risk of heart attacks and stroke.

The idea that the anti-inflammatory effects of statins (and not their cholesterol-reducing effects) may be at the heart of their benefits has been bolstered by work focusing on an inflammatory marker known as C-reactive protein (CRP). Statins are known to have the capacity to reduce CRP levels.

In one study [3] assessing the relationship between statin therapy and cholesterol and CRP levels, it was discovered that “Patients who have low CRP levels after statin therapy have better clinical outcomes than those with higher CRP levels, regardless of the resultant level of LDL cholesterol.” (emphasis mine).

In another study [4] published in the same edition of the journal, statin therapy and cardiovascular disease risk assessed using ultrasound scanning of the inside of the coronary arteries. It was found that “atherosclerosis regressed in the patients with the greatest reduction in CRP levels, but not in those with the greatest reduction in LDL cholesterol levels.”

In yet another study [5] it was found that when treating with statins, those with the highest levels of inflammatory markers at the start of the study derived the most benefit, irrespective of initial cholesterol
levels.

Evidence that statins don’t work through their cholesterol-reducing effect comes from other evidence, including the findings that:

•Statins substantially reduce the risk of stroke, despite the fact that raised cholesterol levels are a weak or non-existent risk factor for stroke [6,7].

•Statins are claimed to reduce CVD risk in individuals who have ‘normal’ or even ‘low’ cholesterol levels [8].

•More intensive cholesterol reduction does not necessarily lead to improved outcomes [9].

Despite what the authors of the recent Lancet review would have us believe, there is considerable evidence that statins primarily work through mechanism that are independent of their cholesterol-reducing effects.

Stepping aside from the science for a moment, let’s also perhaps inject some common sense. Let us not forget that cholesterol is a natural constituent of the body that is a major component in cell membranes, the brain, steroid hormones (including sex hormones) and vitamin D (which appears to have major disease-protective properties). It simply does not make sense to me that driving levels of this key substance to lower and lower levels if, in and of itself, beneficial to health. We would not make the case for driving levels of, say, sodium to lower and lower levels, would we? Or blood sugar levels?

All rationality and common sense seems to fly out of the window when certain doctors and scientists start talking about cholesterol. And when it comes to the science, it’s clear that many are ignorant of or choose to ignore the stacks of evidence that clearly contradict their stance.

References:

1. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 9 November 2010 [epub ahead of print]

2. La Rosa JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425-35

3. Ridker PM, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352(1):20-8

4. Nissen SE, et al. Statin therapy, LDL cholesterol, C-reactive protein and coronary artery disease. N Engl J Med. 2005;352(1):29-38

5. Ridker PM, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998;98(9):839-44

6. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Prospective studies collaboration. Lancet 1995;346(8991-8992):1647-53.

7. Imamura T, et al. LDL cholesterol and the development of stroke subtypes and coronary heart disease in a general Japanese population: the Hisayama study. Stroke 2009;40(2):382-8

8. Ridker PM, et al, JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359(21):2195-2207

9. Kastelein JJ, et al, ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358(14):1431-1443