Thursday, October 31, 2013

Do statins have a role in primary prevention? An update.

Do statins have a role in primary prevention? An update.
Therapeutics Letter Issue 77 / Mar - Apr 2010
Therapeutics Letter #48 (April-June 2003)1 concluded that “statins have not been shown to provide an overall health benefit in primary prevention trials” based on the 5 RCTs8-12 available at that time. More RCTs are now available and 5 systematic reviews2-6 designed to answer this question have been published since 2003. Unfortunately, these reviews do not answer the question “Do the benefits of statins outweigh the harms in people without proven occlusive vascular disease?” This question is critically important to patients, physicians and health care resource utilization.
The Cochrane Collaboration is regarded as the gold standard of systematic reviews. One of its guiding principles is avoiding unnecessary duplication: any independent reviewer following the proper methodology would include the same trials, extract the same data and come to the same interpretation and conclusions. The review is then updated as new trials are published.
The 5 published systematic reviews2-6 (none of which are Cochrane reviews) vary in the RCTs included, summary effect estimates, conclusions and declared conflicts of interest of the authors (Table 1).
Table 1. Published systematic reviews
Two of these reviews report a decrease in total mortality while 3, including the latest, conclude that mortality is not decreased by statins in this setting.
What is the explanation for the different relative risk estimates? In part, it is due to the timing of the review and the trials that were available for inclusion. The 2006 review2 did not have access to 3 RCTs17-19.  The 2007 review3 did not have access to 2 RCTs18,19.  The 2008 review4 did not include 2 RCTs13,19 and included 10 RCTs20-29 not included in any of the other reviews. The 2009 and 2010 reviews5,6 had access to the same RCTs and had very small differences in the RCTs included (Table 1). The reason for the variation in the overall mortality estimate between the 2009 and 2010 reviews is that the 2010 review requested and obtained additional details from authors, allowing exclusion of 3659 secondary prevention patients from 4 large RCTs8,10,11,12.

Why is a new systematic review necessary?

The differences in the interpretation and conclusions of these non-Cochrane reviews are confusing for clinicians. They can be resolved by using Cochrane methodology, including the Cochrane Risk of Bias Tool. Therefore we performed a new systematic review starting with the 22 RCTs included in at least one of these 5 systematic reviews. We excluded 10 of the RCTs20-29 included in the 2008 review because the population studied was largely or entirely people with occlusive vascular disease at baseline. We included the remaining 12 RCTs8-19, which provided data for at least one of 3 outcomes that we judged least subject to bias and most meaningful to patients: total all-cause mortality, total people with at least one serious adverse event (SAE) and total people with at least one major coronary heart disease (CHD) serious adverse event. All-cause mortality is an important outcome, for which we used the more accurate data from the 2010 review. Total SAEs capture overall mortality and all serious morbidity. Major CHD (non-fatal MI and death from coronary heart disease) is the outcome specifically reduced by statins, and less subject to bias than other cardiovascular outcomes such as revascularizations and strokes.
Results. All 12 RCTs report major CHD data, 11 report mortality data and 6 report SAE data. Our meta-analysis demonstrates that the reduction in mortality and major CHD, both SAE outcomes, is not reflected in a reduction in total SAEs (Table 2). The results are similar if they are limited to the 6 RCTs8,9,11,14,16,19 that reported SAEs:  mortality RR 0.90 [0.79-0.98], ARR 0.4%; Major CHD RR 0.70 [0.62-0.79], ARR 1.0%.

 However, getting accurate data entered and analysed is insufficient on its own. Cochrane reviews require assessing the risk of bias for each included RCT using the Risk of Bias Tool. Using this tool we found some risk of bias for each of the 12 included RCTs. Table 2.
Table 2. Statins for primary prevention meta-analysis
Loss of blinding to treatment allocation probably occurred in all 12 RCTs, because statins predictably lower LDL cholesterol and the physicians managing the patients knew the lipid parameters. This loss of blinding likely biased clinical decisions regarding revascularization procedures and how outcomes were categorized (e.g. transient ischemic attack or reversible ischemic neurological deficit). Fewer revascularization procedures in the statin group as a result of loss of blinding would result in fewer complications secondary to the procedures, e.g. myocardial infarctions.
Other risks of bias affected only some RCTs. Of highest risk are the biases due to stopping RCTs early for benefit, affecting 3 RCTs12,14,19, and incomplete outcome reporting bias (not an intention to treat analysis), affecting 1 RCT18. A recent research study demonstrated that the magnitude of the bias effect from stopping RCTs early for benefit is surprisingly large and robust, RR 0.71 [0.66-0.77].7 Testing the effect of this bias estimate on the early terminated JUPITER trial changes the RR for major CHD from 0.54 to 0.76 and completely negates the mortality benefit.
In order to test the effect of the bias from these 4 RCTs we removed them; analysis of the remaining 7 RCTs (Table 2, second row) shows no reduction in mortality. This suggests that the claimed mortality benefit with statins for primary prevention is more likely due to bias than being a true effect. Removing the 4 potentially biased trials also diminished the magnitude of the major CHD relative risk reduction from 26% to 21%.

How can CHD SAEs decrease, but not total SAEs?

All CHD events are SAEs and are counted in both categories. Therefore a reduction in major CHD SAEs should be reflected in a reduction in total SAEs. The fact that it is not suggests that other SAEs are increased by statins negating the reduction in CHD SAEs in this population. A limitation of our analysis is that we could not get total SAE data from all the included RCTs. However, we are confident that the data from the 6 missing RCTs would not change the results, because they represent only 41.2% of the total population and include ALLHAT-LLT10, where one would not expect a reduction in total SAEs; in that trial there was no effect on mortality or cardiovascular SAEs. 


  • Systematic reviews and meta-analyses are challenging and require much more than locating RCTs and plugging in the numbers.
  • The claimed mortality benefit of statins for primary prevention is more likely a measure of bias than a real effect.
  • The reduction in major CHD serious adverse events with statins as compared to placebo is not reflected in a reduction in total serious adverse events.
  • Statins do not have a proven net health benefit in primary prevention populations and thus when used in that setting do not represent good use of scarce health care resources.

The draft of this Therapeutics Letter was submitted for review to 45 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.

  1. Therapeutics Initiative. Do statins have a role in primary prevention? Therapeutics Letter. Apr-Jun 2003; 48:1-2. http://ti.ubc.ca/letter48
  2. Thavendiranathan P, Bagai A, Brookhart MA, Choudhry NK. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch Intern Med. 2006;166(21):2307-2313.
  3. Abramson J, Wright JM. Are lipid lowering guidelines evidence-based? Lancet. 2007;369(9557):168-9.
  4. Mills EJ, Rachlis B, Wu P, et al. Primary prevention of cardiovascular mortality and events with statin treatments. J Am Coll Cardiol. 2008;52(22):1769-1781.
  5. Brugts JJ, Yetgin T, Hoeks SE, et al. The benefits of statins in people without established cardio-vascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ. 2009;338:b2376. doi:10.1136/bmj.b2376
  6. Ray KK, Sreenivasha RKS, Sebhat E, 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. 
  7. Bassler D, Briel M, Montori VM, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA. 2010;303(12):1180-87.
  8. Shepherd J. Cobbe SM. Ford I. Isles CG. Lorimer AR. MacFarlane PW. McKillop JH. Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. New England Journal of Medicine. 333(20):1301-7, 1995 Nov 16.
  9. Downs JR. Clearfield M. Weis S. Whitney E. Shapiro DR. Beere PA. Langendorfer A. Stein EA. Kruyer W. Gotto AM Jr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 279(20):1615-22, 1998 May 27.
  10. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 288(23):2998-3007, 2002 Dec 18.
  11. Shepherd J. Blauw GJ. Murphy MB. Bollen EL. Buckley BM. Cobbe SM. Ford I. Gaw A. Hyland M. Jukema JW. Kamper AM. Macfarlane PW. Meinders AE. Norrie J. Packard CJ. Perry IJ. Stott DJ. Sweeney BJ. Twomey C. Westendorp RG. PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 360(9346):1623-30, 2002 Nov 23.
  12. Sever PS. Dahlof B. Poulter NR. Wedel H. Beevers G. Caulfield M. Collins R. Kjeldsen SE. Kristinsson A. McInnes GT. Mehlsen J. Nieminen M. O'Brien E. Ostergren J. ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 361(9364):1149-58, 2003 Apr 5.
  13. Collins R. Armitage J. Parish S. Sleigh P. Peto R. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 361(9374):2005-16, 2003 Jun 14.
  14. 14. Colhoun HM. Betteridge DJ. Durrington PN. Hitman GA. Neil HA. Livingstone SJ. Thomason MJ. Mackness MI. Charlton-Menys V. Fuller JH. CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 364(9435):685-96, 2004 Aug 21-27.
  15. Asselbergs FW, Diercks GF, Hillege HL, et al; Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) Investigators. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation. 2004;110(18):2809-2816.
  16. Anderssen SA, Hjelstuen AK, Hjermann I, Bjerkan K, Holme I. Fluvastatin and lifestyle modification for reduction of carotid intima-media thickness and left ventricular mass progression in drug-treated hypertensives. Atherosclerosis. 2005;178(2):387-397.
  17. Knopp RH, d'Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care. 2006;29(7):1478-1485.2007;115(1):114-126.
  18. Nakamura H. Arakawa K. Itakura H. Kitabatake A. Goto Y. Toyota T. Nakaya N. Nishimoto S. Muranaka M. Yamamoto A. Mizuno K. Ohashi Y. MEGA Study Group. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet. 368(9542):1155-63, 2006 Sep 30.
  19. Ridker PM, Danielson E, Fonseca FA, 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.
  20. Anonymous. Pravastatin use and risk of coronary events and cerebral infarction in japanese men with moderate hypercholesterolemia: the Kyushu Lipid Intervention Study. Journal of Atherosclerosis & Thrombosis. 7(2):110-21, 2000.
  21. Furberg CD. Adams HP Jr. Applegate WB. Byington RP. Espeland MA. Hartwell T. Hunninghake DB. Lefkowitz DS. Probstfield J. Riley WA. et al. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Circulation. 90(4):1679-87, 1994 Oct.
  22. Holdaas H. Fellstrom B. Jardine AG. Holme I. Nyberg G. Fauchald P. Gronhagen-Riska C. Madsen S. Neumayer HH. Cole E. Maes B. Ambuhl P. Olsson AG. Hartmann A. Solbu DO. Pedersen TR. Assessment of LEscol in Renal Transplantation (ALERT) Study Investigators. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet. 361(9374):2024-31, 2003 Jun 14
  23. Hedblad B. Wikstrand J. Janzon L. Wedel H. Berglund G. Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: Main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS). Circulation. 103(13):1721-6, 2001 Apr 3.
  24. Sawayama Y. Shimizu C. Maeda N. Tatsukawa M. Kinukawa N. Koyanagi S. Kashiwagi S. Hayashi J. Effects of probucol and pravastatin on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia. Fukuoka Atherosclerosis Trial (FAST). Journal of the American College of Cardiology. 39(4):610-6, 2002 Feb 20.
  25. Salonen R. Nyyssonen K. Porkkala E. Rummukainen J. Belder R. Park JS. Salonen JT. Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation. 92(7):1758-64, 1995 Oct 1.
  26. Mercuri M. Bond MG. Sirtori CR. Veglia F. Crepaldi G. Feruglio FS. Descovich G. Ricci G. Rubba P. Mancini M. Gallus G. Bianchi G. D'Alo G. Ventura A. Pravastatin reduces carotid intima-media thickness progression in an asymptomatic hypercholesterolemic mediterranean population: the Carotid Atherosclerosis Italian Ultrasound Study. American Journal of Medicine. 101(6):627-34, 1996 Dec.
  27. Anonymous. Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. The Pravastatin Multinational Study Group for Cardiac Risk Patients. American Journal of Cardiology. 72(14):1031-7, 1993 Nov 1.
  28. Zanchetti A. Crepaldi G. Bond MG. Gallus G. Veglia F. Mancia G. Ventura A. Baggio G. Sampieri L. Rubba P. Sperti G. Magni A. PHYLLIS Investigators. Different effects of antihypertensive regimens based on fosinopril or hydrochlorothiazide with or without lipid lowering by pravastatin on progression of asymptomatic carotid atherosclerosis: principal results of PHYLLIS--a randomized double-blind trial. Stroke. 35(12):2807-12, 2004 Dec.
  29. Mohler ER 3rd. Hiatt WR. Creager MA. Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease. Circulation. 108(12):1481-6, 2003 Sep 23.
Read the complete article here.

Sunday, October 27, 2013

BMJ editor casts doubt on veracity of statin trials funded by the statin makers - Godlee

Statins for all over 50? No

Fiona Godlee, editor, BMJ

BMJ 2013; 347 doi: http://dx.doi.org/10.1136/bmj.f6412 (Published 23 October 2013)                                         Cite this as: BMJ 2013;347:f6412    
Should you prescribe statins to everyone over the age of 50, even those at low cardiovascular risk? A new Cochrane review seems to suggest that you should. An article in this week BMJ cries caution (doi:10.1136/bmj.f6123).

Current guidance from the UK’s National Institute for Health and Care Excellence (NICE) and the American Heart Association recommends statins only when the 10 year risk of cardiovascular disease is 20% or greater. But since these guidelines were written, a large meta-analysis of individual patient data reached a different conclusion. Published in the Lancet in 2012, the Cholesterol Treatment Trialists (CTT) Collaboration meta-analysis found that statins significantly reduced major cardiovascular events and all cause mortality in people at low risk, a benefit which, the paper said, “greatly exceeds any known hazards of statin therapy.”

As John Abramson and colleagues explain, it’s this meta-analysis that led the Cochrane reviewers to embrace the idea that statins should be used far more widely, even perhaps to everyone over 50, as a Lancet editorial suggested at the time.

But Abramson and colleagues’ detailed critique of the CTT meta-analysis should give us pause. Their own analysis of the data finds no evidence of a reduction in all cause mortality or in the total number of serious events. They also highlight the failure of the trials included in the CTT analysis to adequately report important harms of statin treatment, including myopathy and diabetes. They conclude that broadening the use of statins to low risk individuals “will unnecessarily increase the incidence of adverse events without providing overall health benefits.”

There is a concern underlying their critique that will be familiar to BMJ readers. It is that all of the trials included in the CTT meta-analysis were funded by the manufacturer of the statin being studied. They list the various ways in which these trials might have exaggerated the benefits of statins and minimised the harms, and they summarise what low risk patients need to know. Top of the list is the benefit of lifestyle change, something that the dominance of industry sponsored clinical trials too often obscures.

None of this does much to bolster confidence in the published literature. Nor am I reassured by discussions at two recent meetings co-hosted by the European Federation of Pharmaceutical Industry Associations (EFPIA). Drug company AbbVie is suing the European Medicines Agency to stop summary reports of its clinical trials becoming publicly available (doi:10.1136/bmj.f1636). AbbVie’s lawyer made clear that the company considers even the data on adverse events to be commercially confidential. Despite industry’s claims to be in favour of greater transparency, EFPIA and its American counterpart PhRMA are supporting Abbvie. The BMJ and BMA have joined forces to intervene on behalf of the EMA (doi:10.1136/bmj.f4728).

As for a way forward, I can’t improve on the list of solutions proposed by Richard Lehman when emailing out his journal review blog this week (http://bit.ly/HcKvjy): “All phase 3 trials to be designed and conducted independently of manufacturers, using the best available comparator. Research priorities to be determined by patients (James Lind Alliance). Value-based pricing. All data available from all trials, with meta-data: IPD [individual patient data] level for qualified independent centres. Big increase in comparative effectiveness research, much more research into non-pharmacological treatments.”


Cite this as: BMJ 2013;347:f6412


  • Follow BMJ Editor Fiona Godlee on Twitter @fgodlee and the BMJ @bmj_latest
Emphasis added.
Read the complete article here.

Friday, October 25, 2013

Statins do not help you live longer – or do anything much else for that matter - Kendrick

Statins do not help you live longer – or do anything much else for that matter

Sometimes you read a thing quickly, and then you have to read it again to make sure you read it right. Yesterday I was sent a copy of a ‘Patient page’ from the Journal of the American Medical Association (JAMA).  The page was from the April 3rd 2013 edition, pp 1419. It is stamped ‘JAMA – copy for your patients’. JAMA is one of the highest impact medical journals in the world.

This patient page states that:
‘One question involves disagreement about whether the statin side effects are merely uncomfortable or actually pose significant health risks. The other question is whether reducing bad cholesterol will actually help you live longer than you otherwise would. Some of this disagreement involves how physicians interpret the results of studies. However, a 2010 analysis combined the results of 11 studies and found that taking statins did not lower the death rate for people who did not have heart disease. If your physician recommends taking a statin, talk to him or her about the risks and benefits for your individual situation.’
For many years I have been ridiculed by colleagues for saying that, if you do not already have established heart disease, statins do not increase your life expectancy. By which I mean that they don’t’ actually work. ‘Don’t be ridiculous.’ Is what they exclaim to me. I usually reply that the evidence is pretty clear, and always has been. But I know that they don’t believe me.

Recently, without warning, one of the most influential medical journals in the world turned round and confirmed it. JAMA has stated in black and white that if you do not have established heart disease e.g. angina, previous heart attack, you will not live any longer if you take a statin.

Frankly, I think JAMA will now come under ever increasing bombardment from the ‘experts’ and will end up retracting this statement. In fact, I am willing to bet that they will – having now seen some of the outraged letters sent in. However from time to time the truth – like a small grass shoot growing through a concrete pavement – will emerge. As it did in April.

(I should add, at this point, that around 95% of people who take statins do not have established heart disease.)

However, wrapped up in this issue, is an inevitable argument. I know this argument well, for I have heard it a thousand times. ‘Ah, but it is not just death we are talking about here…. statins prevent non-fatal heart attacks and non-fatal strokes and suchlike. These are terrible things that damage the quality of your life. Medicine is not only about getting people to live longer, it is also about quality of life. Preventing a non-fatal stroke is extremely important, and statins do this.’ In other words, statins don’t make you live longer, but they do provide other, very significant benefits, by preventing Serious Adverse Events (SEAs).

This is a good argument. At least it would be if it were true. However, we have no idea about whether it is true or not. For the simple reasons that the data on SEAs is almost entirely hidden from view. Data on SEAs are considered so commercially sensitive that, in most jurisdictions, pharmaceutical companies won’t release them (and don’t have to release them), even if you ask nicely*.

Before moving onto that issue, I know that I need to explain I am talking about here in a little more detail, and clear up a bit of confusion with the nomenclature. For in the area of adverse events/effects, we have two terms that sound very similar, but mean very different things.

Firstly, there are drug related adverse effects. These are often called ‘side-effects’. But side effects can be good, or bad. For example Viagra was developed as an angina drug but it was found to create enhanced erections, as a side-effect. [You can decide if this is a beneficial side-effect or not]. Viagra also causes headaches. This is also a side-effect, but it would be more accurate to call it a drug related adverse effect.

Drug related adverse effects = negative/unpleasant ‘side-effects’ of a drug
A Serious Adverse Event (SEA) may sound similar to a drug related adverse effect, but it means something completely different. An SEA is a significantly bad thing that a drug might prevent e.g. non-fatal heart attack. Or, it could be something that the drug causes e.g. rhabodmyolysis (muscle breakdown), followed by kidney failure. Which is something that is known to be caused by statins.
SEAs can therefore be good, or bad. Depending on whether they are caused by, or prevented by, the drug. This means that there is absolutely no point in presenting figures on SEAs prevented by statins, without knowing if they caused an equal number of SEAs at the same time.

Completely unsurprisingly, whilst we are bombarded with statistics about how many SEAs are prevented by statins, we have very little idea about how many SEAs are caused by statins. Because in most countries, these data are not released. Its’ commercially sensitive dontcha know. [Damned right it’s commercially sensitive. If the public saw these data they would stop taking half their meds overnight.]

There have, however, been glimpses of SEAs with statins – when the data escaped from the clutches of the pharmaceutical companies. When the Cochrane collaboration fist looked at primary prevention studies, two of the five major studies did report ‘negative’ SEAs (although they did not say what the SEAs were, and still won’t). In these two trials AFCPAS and PROSPER, the SEAs were:

Statin arm:      44.2%Placebo arm:  43.9%
‘In the 2 trials where serious adverse events are reported, the 1.8% absolute reduction in myocardial infarction and stroke should be reflected by a similar absolute reduction in total serious adverse events; myocardial infarction and stroke are, by definition, serious adverse events. However, this is not the case; serious adverse events are similar in the statin group, 44.2%, and the control group, 43.9% This is consistent with the possibility that unrecognized serious adverse events are increased by statin therapy and that the magnitude of the increase is similar to the magnitude of the reduction in cardiovascular serious adverse events in these populations.’  (read more…)
In short there were slightly more SEAs in those taking statins than in those taking placebo. Slightly more harm than good.

So what do we now know? We know that if you do not have established heart disease, and you take a statin, you will:
  • not live any longer
  • not avoid major Serious Adverse Events
Which means that there is no possible improvement in either the quality, or the quantity, of life. On the other hand there is a good chance that you will suffer from significant adverse effects e.g. muscle pain, joint pain, impotence, stomach upset, rashes etc. etc. On balance therefore we can state that, if you do not have established heart disease, statins provide no benefits on any important outcome. All they can do is to give you adverse effects. ‘Oh boy, that sounds like a great deal doc. Can’t wait, can’t wait, can I get them now?’

*Please see petition that I just put up on my blog. This petition arrived coincidentally as I was writing this article. At present the European Medicines Agency (EMA), will provide SEA data if requested (with huge persistence). The UK authorities will not release these data, nor will the FDA in the states. A recent move by the pharmaceutical industry is now threatening that the EMA will be forced to hide SEAs. ‘Six months ago two US pharmaceutical companies AbbVie and InterMune took a legal action against EMA that has closed down access to all trial data for all drugs for all doctors and researchers anywhere in the world.’

Closed down all access to all trial data for all drugs for all doctors and researchers anywhere in the world.

That statement is worth repeating. Be afraid, be very afraid indeed. And sign the petition please. Oh, and write to your MEP, as I am now doing.
Read the complete article here.

Thursday, October 24, 2013

Saturated fat is not the major issue - Malhotra

Saturated fat is not the major issue

BMJ 2013; 347 doi: http://dx.doi.org/10.1136/bmj.f6340 (Published 22 October 2013)
Cite this as: BMJ 2013;347:f6340

Let’s bust the myth of its role in heart disease

Scientists universally accept that trans fats—found in many fast foods, bakery products, and margarines—increase the risk of cardiovascular disease through inflammatory processes.1 But “saturated fat” is another story. The mantra that saturated fat must be removed to reduce the risk of cardiovascular disease has dominated dietary advice and guidelines for almost four decades.

Yet scientific evidence shows that this advice has, paradoxically, increased our cardiovascular risks. Furthermore, the government’s obsession with levels of total cholesterol, which has led to the overmedication of millions of people with statins, has diverted our attention from the more egregious risk factor of atherogenic dyslipidaemia.

Saturated fat has been demonised ever since Ancel Keys’s landmark “seven countries” study in 1970.2 This concluded that a correlation existed between the incidence of coronary heart disease and total cholesterol concentrations, which then correlated with the proportion of energy provided by saturated fat. But correlation is not causation. Nevertheless, we were advised to cut fat intake to 30% of total energy and saturated fat to 10%.”3 The aspect of dietary saturated fat that is believed to have the greatest influence on cardiovascular risk is elevated concentrations of low density lipoprotein (LDL) cholesterol. Yet the reduction in LDL cholesterol from reducing saturated fat intake seems to be specific to large, buoyant (type A) LDL particles, when in fact it is the small, dense (type B) particles (responsive to carbohydrate intake) that are implicated in cardiovascular disease.4

Indeed, recent prospective cohort studies have not supported any significant association between saturated fat intake and cardiovascular risk.5 Instead, saturated fat has been found to be protective. The source of the saturated fat may be important. Dairy foods are exemplary providers of vitamins A and D. As well as a link between vitamin D deficiency and a significantly increased risk of cardiovascular mortality, calcium and phosphorus found commonly in dairy foods may have antihypertensive effects that may contribute to inverse associations with cardiovascular risk.6 7 8

One study showed that higher concentrations of plasma trans-palmitoleic acid, a fatty acid mainly found in dairy foods, was associated with higher concentrations of high density lipoprotein, lower concentrations of triglycerides and C reactive protein, reduced insulin resistance, and a lower incidence of diabetes in adults.9 Red meat is another major source of saturated fat. Consumption of processed meats, but not red meat, has been associated with coronary heart disease and diabetes mellitus, which may be explained by nitrates and sodium as preservatives.10

The notoriety of fat is based on its higher energy content per gram in comparison with protein and carbohydrate. However, work by the biochemist Richard Feinman and nuclear physicist Eugene Fine on thermodynamics and the metabolic advantage of different diet compositions showed that the body did not metabolise different macronutrients in the same way.11 Kekwick and Pawan carried out one of the earliest obesity experiments, published in the Lancet in 1956.12 They compared groups consuming diets of 90% fat, 90% protein, and 90% carbohydrate and showed that the greatest weight loss was in the fat consuming group. The authors concluded that the “composition of the diet appeared to outweigh in importance the intake of calories.”

The “calorie is not a calorie” theory has been further substantiated by a recent JAMA study showing that a “low fat” diet resulted in the greatest decrease in energy expenditure, an unhealthy lipid pattern, and increased insulin resistance in comparison with a low carbohydrate and low glycaemic index diet.13 In the past 30 years in the United States the proportion of energy from consumed fat has fallen from 40% to 30% (although absolute fat consumption has remained the same), yet obesity has rocketed.

One reason: when you take the fat out, the food tastes worse. The food industry compensated by replacing saturated fat with added sugar. The scientific evidence is mounting that sugar is a possible independent risk factor for the metabolic syndrome (the cluster of hypertension, dysglycaemia, raised triglycerides, low HDL cholesterol, and increased waist circumference).

In previous generations cardiovascular disease existed largely in isolation. Now two thirds of people admitted to hospital with a diagnosis of acute myocardial infarction really have metabolic syndrome—but 75% of these patients have completely normal total cholesterol concentrations.14 Maybe this is because total cholesterol isn’t really the problem?

The Framingham heart study sanctified total cholesterol as a risk factor for coronary artery disease, making statins the second most prescribed drug in the US and driving a multibillion dollar global industry. In the United Kingdom eight million people take statins regularly, up from five million 10 years ago. With 60 million statin prescriptions a year, it is difficult to demonstrate any additional effect of statins on reduced cardiovascular mortality over the effects of the decline in smoking prevalence and primary angioplasty.15

Despite the common belief that high cholesterol is a significant risk factor for coronary artery disease, several independent population studies in healthy adults have shown that low total cholesterol is associated with cardiovascular and non-cardiac mortality, indicating that high total cholesterol is not a risk factor in a healthy population.16 17 18

A recent “real world” study of 150 000 patients who were taking statins showed “unacceptable” side effects—including myalgia, gastrointestinal upset, sleep and memory disturbance, and erectile dysfunction—in 20% of participants, resulting in discontinuation of the drug.19 This is massively at odds with the major statin trials that report significant side effects of myopathy or muscle pain in only one in 10 000.

A meta-analysis of predominantly industry sponsored data reported that in a low risk group of people aged 60-70 years taking statins the number needed to treat (NNT) to prevent one cardiovascular event in one year was 345.20 The strongest evidence base for statins is in secondary prevention, where all patients after a myocardial infarction are prescribed maximum dose treatment irrespective of total cholesterol, because of statins’ anti-inflammatory or pleiotropic (coronary plaque stabilising) effects. In this group the NNT is 83 for mortality over five years. This doesn’t mean that each patient benefits a little but rather that 82 will receive no prognostic benefit.21 The fact that no other cholesterol lowering drug has shown a benefit in terms of mortality supports the hypothesis that the benefits of statins are independent of their effects on cholesterol.

Adopting a Mediterranean diet after a heart attack is almost three times as powerful in reducing mortality as taking a statin. The recently published PREDIMED randomised controlled trial was stopped early after it showed that in high risk people the Mediterranean diet achieved a 30% improvement over a “low fat” diet in terms of cardiovascular events.22

Pharmacotherapy can assuage the symptoms but can’t alter the pathophysiology. Doctors need to embrace prevention as well as treatment. The greatest improvements in morbidity and mortality have been due not to personal responsibility but rather to public health. It is time to bust the myth of the role of saturated fat in heart disease and wind back the harms of dietary advice that has contributed to obesity.


Cite this as: BMJ 2013;347:f6340
Read the complete article here.

Read also - Top heart doctor: Unprocessed fatty foods may actually be good for you

Watch this excellent video on saturated fat and heart disease. http://www.abc.net.au/catalyst/stories/3876219.htm
Here are some quotes from the video:

Dr Johnny Bowden
"Sugar is far more damaging to the heart than fat ever was, and we're beginning to see this now. So, this focus on cholesterol has been incredibly destructive because we haven't looked at these real promoters of heart disease - inflammation, oxidative damage, sugar in the diet, and number one with a bullet - stress."

Dr Johnny Bowden
"Margarine is the perfect example of the stupidest nutritional swap-out in history. We had this trans fat-laden crappy manufactured product that we were eating because we were so phobic about saturated fat and cholesterol."

Dr Stephen Sinatra
"To switch to polyunsaturated fats with the vegetable oils, that's horrific advice. The polyunsaturated fats, the vegetable oils, these omega-6 oils, are inflammatory because they're very prone to oxidation."

Dr Stephen Sinatra
"It took decades to really entrench this myth. It's probably going to take a few more decades to get us out of this myth. But to vilify saturated fats I think is one of the worst things the medical profession has done."

Dr Ernest Curtis
"I'd love to see the medical establishment saying, 'Whoops, we were wrong'. That's not going to happen. Frankly, that generation is going to have to die off, and perhaps the generation coming up can do better."

Wednesday, October 9, 2013

Statins Linked to Cataracts in Large, Retrospective Study

Statins Linked to Cataracts in Large, Retrospective Study

 Sep 20, 2013
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.
Read the complete article here.

Tuesday, October 8, 2013

The topic covered in this podcast concerns the use of the B vitamin , Niacin, when taking a statin. Is this a beneficial combination, or does it lead to an increased risk of stroke? We invite you to listen in with Lindsay and Dr. Blanchet.


Fish oil, sterol absorption, and Zetia - Blanchet

Dr. Blanchet podcast on fish oil and sterol absorption re heart disease.


Questions -
     Are you a hyper absorber of plant sterols?
     What is optimal range of EPA/DHA intake?
     What about Zetia?

So much for scientific debate - Kendrick

   So much for scientific debate

I thank Ted Hutchinson for pointing me at this article in the Irish Independent. It appeared on the 5th of October, and I reprint it in full, here.

A LEADING vascular surgeon, whose research review concluded cholesterol-lowering medicines may do more harm than good for many otherwise healthy people, has been gagged by the Health Service Executive.
Sherif Sultan, a senior medic at University College Hospital, Galway, reviewed a range of studies of statins and found a lack of evidence to show they should be given as a means of prevention to healthy people with high cholesterol but no heart disease.

Mr Sultan and his surgeon colleague Niamh Hynes said lifestyle changes to reduce cholesterol were better because this allowed people to avoid the risk of statins’ side effects.
However, in a statement last night, Dr Pat Nash, a cardiologist and the group clinical director in University College Hospital said the recently published views of his colleagues were “not representative” of those in Galway or neighbouring hospitals.
“As group clinical director of the West/North West Hospitals Group, and a working cardiologist, I wish to reassure patients that statins are safe,” said Dr Nash.
“These are very important, well-validated drugs for the treatment of elevated cholesterol. We have extensive evidence to show their benefit and to show that they improve outcomes for patients with heart disease and stroke and that they have a role in preventing heart disease and stroke.
“As always, if patients have any concerns, they should not discontinue their medication without discussing with their GP or consultant.”      
Asked to comment, Mr Sultan said: “I have received an official warning from the HSE and have been instructed not to liaise directly with the press in my capacity as a HSE consultant.” However, he said he could continue to comment as a consultant vascular surgeon at the Galway Clinic, where he has a private practice.
The HSE declined to comment on the reasons for ordering Mr Sultan not to speak as a public consultant. He said he stood by his analysis of the role of statins in otherwise healthy patients with high cholesterol. He pointed to another recently published review on exercise versus drug therapy in the management of pre-diabetes and cardiovascular disease.
“That ‘British Medical Journal’ analysis showed the superiority of exercise over drug therapy extends even to secondary prevention (where patients have developed disease)1.
This story has been rumbling on for a while. A report on the research paper can be found in the Irish Medical Times from a couple of weeks before.

The under-reporting of findings on major adverse effects of statin therapy and the way in which they had been withheld from the public, and even concealed, is a scientific farce, claims new Irish research.
Mr Sherif Sultan, Consultant Vascular and Endovascular Surgeon, and Niamh Hynes, Clinical Lecturer In Vascular and Endovascular Surgery, claimed their study, just published in the Journal of Endocrine and Metabolic Diseases (2013, 3, 179-185) highlights the major side-effects and dangers of statins.
They said there is a categorical lack of clinical evidence to support the use of statin therapy in primary prevention. They are both based in the Western Vascular Institute at University College Hospital Galway and the Galway Clinic. “Odds are greater than 100-to-1 that if you’re taking a statin, you don’t really need it2..
I was sent the original paper by Sherif Sultan a couple of months ago, and it is very scathing about statins….. very scathing indeed. It even suggests, perish the very thought, that pharmaceutical companies may have been trying to present statins in the best light possible. I find such a suggestion almost impossible to believe. Knowing how completely ethical these companies are.
Anyway, I suppose the key phrase in all of this sorry episode is the following:

The HSE declined to comment on the reasons for ordering Mr Sultan not to speak as a public consultant.”
If the Health Service Executive were to comment, what could they say to justify their actions?
The hell with scientific debate. He should just damned will shut up and say what we want him to say?”
“How dare anyone criticise the sainted statins which work in mysterious ways their wonders to perform.”
We expect utter loyalty from those who work in the glorious Irish Health Service. Those who do not support us can expect serious sanctions……”

On balance, declining to comment is probably the best policy for the HSE. Because if you start trying to justify why you are gagging a researcher for trying to tell the truth then, well, you will end up having to justify state censorship of scientific debate. Which never looks that good on the printed page, I find.

I feel I should sign off this blog with a quote from George Orwell, taken from 1984. “Being in a minority, even in a minority of one, did not make you mad. There was truth and there was untruth, and if you clung to the truth even against the whole world, you were not mad.”

1: http://www.independent.ie/irish-news/hse-gags-surgeon-after-cholesterol-drug-claims-29636095.html
2: http://www.imt.ie/news/latest-news/2013/09/study-claims-to-highlight-the-ugly-side-of-statins.html
Read the complete article here.

Monday, October 7, 2013

Increased blood levels of Lp-PLA2 have been linked to increased risk for...

Lp-PLA2 (Lipoprotein-Associated Phospholipase A2)
Clinical Use
  • Assess risk of coronary heart disease and cardiovascular disease
  • Assess risk of stroke
Clinical Background
Traditional markers of lipidemia identify only about half of the individuals at risk of cardiovascular disease (CVD).1 Atherosclerosis is now recognized as an inflammatory disease, and inflammatory markers, most notably high-sensitivity C-reactive protein (hs-CRP), have been shown to identify additional individuals who are at risk. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is another marker of vascular inflammation, and because it is not associated with systemic inflammation it is more vascular-specific than is CRP.2 It is produced by macrophages and other inflammatory cells and is found in atherosclerotic lesions.
Increased blood levels of Lp-PLA2 have been linked to increased risk for: 1) cerebral thrombosis,3 2)
first4 and recurrent5 coronary events, 3) adverse prognosis after acute coronary syndrome,6 and 4) CVD associated with metabolic syndrome7 or type 2 diabetes mellitus.8 Evidence from more than 25 prospective studies has shown an approximate doubling of risk for coronary artery disease (CAD), CVD, and stroke when comparing Lp-PLA2 values in the top quintile versus the bottom quintile.2 The predictive value typically remains after adjustment for LDL-cholesterol and other established CVD risk factors.2
Thus, a consensus panel has recommended testing Lp-PLA2 as an adjunct to traditional risk factor assessment in individuals with moderate or high risk of CVD as defined by Framingham risk scores.9 According to the recommendation, an elevated Lp-PLA2 (ie, >200 ng/mL) suggests an individual’s risk is actually higher than that determined using Framingham risk scores, and more intensive therapy would be appropriate.9 For example, an individual with a moderate Framingham risk score and an elevated Lp-PLA2 may be reclassified as being at high risk, and the LDL-cholesterol goal would then be reduced from <130 dl.="" dl="" mg="" sup="" to="">9
The individual would also receive recommendations for more intensive life-style changes. Similarly, in individuals with an elevated Lp-PLA2 and high Framingham risk score, the LDL-cholesterol goal would be reduced from <100 dl.="" dl="" mg="" sup="" to="">9 Note that others have recommended a Lp-PLA2 cut point of 235 ng/mL, which coincides with the 50th percentile of the U.S. population, rather than the 200 ng/mL recommended by the consensus panel.10
The consensus panel further recommends use of Lp-PLA2 to refine risk for stroke.9
Screening with both Lp-PLA2 and hs-CRP may provide a better risk assessment for CVD and stroke than using either test alone. Elevated levels of Lp-PLA2 and hs-CRP were independent and complementary in identifying increased risk for future coronary events among healthy middle-aged men4 and patients with CVD.11
Read the complete article here.
Also listen to The Tuesday Talk Show where Dr William Blanchet discusses Lp-PLA2 here.

All heart attacks and strokes are preventable! Bale - Doneen

"Superior health care providers prevent disease. Mediocre providers treat the disease before it is evident. Inferior providers treat the full blown disease"

All heart attacks and strokes are preventable!

Forget Cholesterol, Inflammation's the Real Enemy - CBN.com