FOAM4GP Map – To Statin or not to Statin? – That is the question.

Statin Confusion!

I am questioning my statin prescribing and need to be able to justify what I am doing with my patients (which I should have been able to anyway but Catalyst has brought this to the fore – Link). I feel I have been doing a medical practice which I was taught, without fully knowing the evidence. Time to rectify this.

DISCLAIMER: I have not received any drug company monies for any of the links below or from anti-statin campaigners. Nor do I get visits from drug company reps. I don’t even own a pen!Prof Montage

Lets start with a fun 3D video from Prof Montage introducing statistics with statins in the elderly – Link

Question 1 – What is the mechanism of action behind how HMG-CoA Reductase Inhibitors (statins) work?

Here is a 4 minute refresher video on Statin’s MOA – HMG-CoA Reductase InhibitorsLink

Question 2 – Who should I be testing the cholesterol of in the first place?

RACGP Red book recommends that adults should have their fasting lipids measured at age 45 and every 5 years in a context of absolute risk assessment. Aboriginal and Torres Strait Islander adults should be Red Bookassessed every 5 years from 35yo – Link

Question 3 – What is the evidence for the use of Statins in primary prevention (i.e. they have not had an AMI)?

A Cochrane review from 2011 on the use of Statins for PRIMARY prevention of cardiovascular disease sits beautifully on the fence to watch the fight unfold – Link

The Guidelines for the management of Absolute Cardiovascular Disease Risk published in 2012 are here – Link. Heart Foundation

They claim “High plasma cholesterol is a well-known modifiable risk factor for CVD.” and they discuss this claim on page 42-46. This is very detailed and I recommend a read. If you don’t want to read then there is a video version by National Heart Foundation (NHF) here – Link

They mention “An important result of the studies reported here is that the benefits of lipid-lowering therapy depend on the initial levels of risk: the absolute reductions in risk were highest in people at the highest baseline risk irrespective of initial lipid levels.” This leads to question 2.

Many studies have shown a decrease in all cause mortality with Statins as is summarised here by Medscape – Link. I Medscapealways found this amusing – so if I take a statin I am less likely to get run over by a car? (Joke disclaimer – no evidence to back up this claim nor am I going to run a trial!)

Question 4 – How do I know when and who to prescribe Statins?

Statin prescribing is supposed to be management of a modifiable risk Absolute Risk Calculatorfactor when used in conjunction with assessment of a total patients absolute risk of cardiovascular disease (CVD). To risk stratify, I use the Absolute cardiovascular risk calculator supported by Diabetes Australia, Kidney Health Australia, Heart Foundation, and Stroke Foundation – Link – The basis behind this is that patients at high risk of CVD will benefit greater than those at lesser risk.

FraminghamI can use the colourful Framingham risk calculator chart from NHF to see if reducing my patients cholesterol will actually reduce their overall CVD risk and this has a good flow chart for prescribing Statins – Link

The PBS wilPBSl only subsidise Statin’s for patients at higher risks. Have a look at the PBS flow chart – Link

Question 5 – I noticed the guidelines mention ‘Checking for treatable secondary causes of hyperlipidaemia’. What are these?

In the long version of the NHF 2012 guidelines they include: Diet, Alcohol, Hypothyroidism, Diabetes, Liver disease, Nephrotic syndrome, and Steroid treatment.

Question 6 – What about patients who I cannot use the calculator on and what does it not consider?Needs research

There is a group of patients who are ALREADY known to be high risk so do not need risk assessment. They are listed here – Link

Also, the predictive value has not been assessed in a specifically overweight population (which the majority of these people are?)

If the patient has AF then they are “more likely” to be high risk (this is mentioned but not made clear in the guidelines)

Also, the guidelines state that they recognise there are other risk factors but these were either not studied or not in the study. Factors such as: socioeconomic status, family history, cultural and ethnic identity, waist circumference, BMI, nutrition, alcohol intake, physical activity level. I think we are meant to just guess that these might alter risk?? I don’t like guessing… Looks like an area for future research.

The other consideration is patients >74yo who cannot be placed on the calculator. Does this mean elderly do not have heart attacks? Quite the opposite. There is just a paucity of good evidence either way. We do know that side effects increase in the elderly eg. Myopathy can be much more debilitating in the elderly who are at risk of falls. Also, bizarrely there seems to be increased all cause mortality in the elderly with a Total Cholesterol (TC) UNDER 5.5 – Study in Age Ageing 2011 – Link. The evidence is fairly weak but I think you would have to think twice about prescribing primary prevention in a patient over 75yo. NPS talks about the debate here – Link.

Question 7 – What are the arguments against Statins?

Michael Tam of FOAM fame writes in the Medical Observer a very good article on the Medical Observerlack of evidence on the use of statins in Low risk patients – Link

I had difficulty finding a well constructed argument against statins in general. A lot Cholesterol Conof the sites quoted individual studies supporting their argument and rubbished conflicting evidence – most were selling anticholesterol books.

A more balanced argument is in the Wall Street Journal 2012 – LinkWall Street Journal

Most of the discussion against statins, including in this BMJ article, – Link – talk about the lack of evidence for use of Statins in Low/Intermediate risk patients.

My understanding is that based on Australian guidelines these patients are not supposed to be prescribed statins anyway? I’m getting confused about whether there is anyone ACTUALLY arguing with anyone about this? We seem to agree on this.

Cochrane news has a rather amusing take on the Statin discussion and Cochraneevidence vs eminence –  “In God We Trust; all others must show data”. – Link

Question 8 – What can go wrong with Statins?

Statin Myopathy – 10-15% of patients get mild to severe symptoms any time after starting statins. Evidence is discussed in Medscape – Link

Statin induced T2DM – Recent BMJ article in 2013 showed a mild link in observational data from Canada. I cannot get free access to BMJ article but it is summarised here by Medical News Today – Link. Note there were different risks for different Statins! Also, possibly confounding factors (eg. Higher cholesterol and Diabetes may be linked with obesity).

Hepatotoxicity – Essentially can cause serious liver problems in approximately 1:1,000,000. Journal article in Heart Views 2011 discusses this – Link

Dementia – Confusion in Australia about an FDA statment has led to this discussion. Alzheimer’s Australia official statement reiterates that there is no recognised link between fixed or progressive dementia and Statins. This is confusion from FDA statement saying some patients experienced “reversible generally non-serious confusion and memory loss when on Statins”. – Link

Question 9 – What monitoring do I need to do for a patient on a Statin?

Therapeutic Guidelines 2013 suggest baseline CK and LFTs –> Assess response and repeat LFTs and CK at 1-2 months.Therapeutic Guidelines Cholesterol levels can also be checked at this time and the dose titrated. NHF recommends reassessment of cholesterol on a 6-12 mth basis for assessing adherence and cholesterol levels – Link

If CK 10x normal (or 5x with symptoms) stop or reduce dose and retest at 1 month.

If ALT 3x normal then stop therapy or reduce dose and retest at 1 month.

If symptoms and elevations were mild then can restart the medication at a lower dose or start a different type or move to a different group (eg. fenofibrates).

Check local drug guides for further details (eg. MIMs, eTG).

Question 10 – What do I do if someone is intolerant?

Discussed here in this good Australian Doctor article – Link. EssentiAustralian Doctorally withdrawing the drug and reintroducing slowly OR changing to a different class eg. Ezetimbe.

Question 11 – What about evidence of use in secondary prevention?

The NNT reviewed Statins given for 5 years for heart disease prevention The NNTin patients with known heart disease. Treat 83 to save 1 life. Treat 39 to prevent 1 non-fatal heart attack. Treat 125 to prevent 1 stroke. Conversely treat 10 for 1 harm (muscle damage). Treat 167 for 1 T2DM – Link

The BMJ trial here discusses also the previous studies on Statin’s in secondary prevention. The evidence seems fairly robust reducing risk of death by approximately 30% (eg. LIPID, 4S, CARE, GISSI-P studies) – Link

For patients for secondary prevention the target LDL is <1.8 (NHF).

Question 12 – Which statin has better evidence?

Much of a muchness. Discussed here half way down the page by NPS – NPS MedicineLink

Question 13 – How do I talk to patients about the lifestyle ways of reducing cholesterol?

There is a great article here by NPS 2011 which discusses the different lifestyle and non-pharm ways of reducing cholesterol – Link

RACGP SNAP guidelines are here – Link

Question 14 – Does diet control make much difference?

A great article in the Canadian Journal of Cardiology 2011 looked at many different diets and their effects on Lipid profile. They found evidence to recommend the following diets: Mediterranean and Portfolio diets; low-fat diet; diet high in soy protein, fibre, or phytosterols; whole grain foods, and omega-3 fatty acid Food Pyramidsupplementation – none of which I found surprising. They also say you can consider consuming nuts, a diet high in carbohydrates and protein, green tea, and red wine, as well as the supplementation with policosanol and red yeast rice extract for improvement of the lipid profile. These ones were out – guggulipid, garlic, chromium, vitamin C, magnesium-pyridoxal-phosphate-glutamate, tocotrienols, and absorbitol cannot be recommended. – Link

I generally recommend the common sense approach and that old pyramid picture which I like for healthy eating anyway!

Question 15 – What about triglycerides?

I’m tired now – haven’t we had enough controversy? Seems this question is even murkier. Here is an article by AAFP 2011 supporting the treatment of triglycerides – Link

National Heart Foundation states there is currently class C evidence to treat elevated triglyceride levels with a fenofibrate, nicotinic acid or fish oil. I think this means someone needs to do more homework? – LinkMy TG

There is quite a good website on patient information for triglycerides here – Link

Question 16 – What is my final reply to the “Catalyst” questioners?Catalyst

Here is a great summary response from the National Heart Foundation – Link

ADDIT (6/11/13) – A colleague has sent me a very interesting link about the catalyst’s experts and their possible links to anticholesterol books and selling nutritional supplements. Good discussion by the “sceptical nutritionist.” I am not endorsing this but showing all sides of the argument – Link

Remember to remind your patients to take their Statin’s if prescribed. Only 40% of patients were still taking their statins at 12 mths and 50% of these stopping before 3 months. Mainly because they were unconvinced of their use (and may have watched Catalyst!)

Simons LA, Levis G, Simons J. Apparent discontinuation rates in patients prescribed lipid-lowering drugs. Med J Aust 1996;164:208–11.

Concluding remarks

I am feeling comfortable that in patients for primary prevention of CVD I will assess them using the Framingham / Absolute Cardiovascular Risk Calculator. Then, if they are low or intermediate risk I will discuss lifestyle factors and targets to aim for in 6 mths with help of the NPS suggestions, SNAP, and NHF guidelines.

If they are high risk I will discuss with them the research supported benefit of going on a statin and also the possible negatives and let them decide. I will perform baseline LFTs and CK and follow them up in 1-2 mths. I will then support their use of statins with regular follow up while modifying other risk factors and supporting lifestyle change.

If they become symptomatic I might consider stress testing just as in the previous FOAMed Map – Link (selfless plug).

Finally, if thoroughly confused and annoyed at the grey and uncertainty of medicine (welcome to GP) then check out Broomedocs advice to his registrars – Link

And Genevieve Yates singing her heart out – Link

Thanks everyone! Please leave a comment so I can find out if these are useful and how to change them in the future! Cheers, Rob!

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14 thoughts on “FOAM4GP Map – To Statin or not to Statin? – That is the question.

  1. What an excellent summary, Rob, served with lashings of evidence and a sprinkling of humour.
    And thanks for the plug 🙂
    I’m now thinking the Catalyst shows did us GPs a favour – has forced us to examine the evidence more comprehensively and critically, and look at our prescribing habits/ advice we give patients. Hopefully we will be able to assist and advise our patients better as a result.

    • Hi Genevieve,

      Thanks for the comments. ‘Catalyst’ may be a catalyst for me to do many more of these FOAM Maps to guide GP colleagues around the Web to present the best links, interesting facts, and hard evidence, on a range of topics. General Practice needs more FOAM – we are behind our amazing ED colleagues who have grabbed hold of this media and ran!

      Cheers, Rob.

  2. Thanks for taking the time for all those useful links ( I have seen most of them but nice to have them in one place for easy review). Just a comment on TG’s – the easiest and quickest way to drop TG’s is to reduce dietary carbohydrate (done it myself). Most people are eating huge amounts – toast and cereal for breakfast, sandwiches and the like for lunch, pasta/rice and spuds for dinner. This doesn’t include snacking on those low fat diet foods, diet yoghurts, lattes and flat whites, etc etc.
    See AHA scientific statement ‘Dietary Sugars Intake and Cardiovascular Health’ esp pg1014 – effects of dietary sugars on BP, Lipids and inflammation: http://www.ncbi.nlm.nih.gov/pubmed/19704096‎

    • Hi Pam,

      Great information – thank you. I have pasted below some relevant quotes from the paper (published in Circulation – Journal of AHA – 2009). Seems like the evidence is leaning towards suggesting a diet decreased in sucrose, glucose, and fructose may decrease levels of triglycerides.

      “Elevations in fasting plasma triglycerides, principally very-low-density lipoproteins, are a consistent feature of diets high (>20% of energy) in sucrose, glucose, and fructose.”

      “In the Women’s Health Initiative, the higher-carbohydrate diet had no effect on triglycerides or high-density lipoprotein cholesterol.50”

      The pathophysiology is suspected to be for several reasons. “These include increased de novo lipogenesis in the liver,31,51,55 increased hepatic triglyceride synthesis, and secretion of very-low-density lipoproteins,53 as well as reduced lipoprotein lipase activity at the adipocyte, which decreases the rate of peripheral triglyceride clearance.51,53”

      “In summary, although the mechanisms are unclear, relative to other carbohydrate sources, sugar intake appears to be associated with increased triglyceride levels, a known risk factor for coronary heart disease; however, relative to other sources of carbohydrate, the effects of sugar intake on high-density lipoprotein and low-density lipoprotein levels remain unclear.”

      Cheers, Rob.

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  4. Great summary Rob!

    A few comments… The evidence for the benefit of LFT and CK monitoring for statins is poor, and the rationale for doing so is questionable in light of the accumulated safety data for statins. An argument can perhaps be made for baseline LFT (even in otherwise fit and well people), but the utility of a baseline CK is rather low in someone not at high risk of myopathy. Stopping a statin in someone who is at mod/high CVD risk, due to an asymptomatic rise in CK, probably does more harm than good.

    We need to recognise that most of us (me included!) have an intrinsic bias to do biometric testing (rather than not) when there is uncertainty. We are always going to get apparent good patient outcomes by Identifying and labelling non-disease. This type of practice is far from harmless, however, and contributes to overdiagnosis, overtreatment, and medicalising the human condition. For instance, we generally vastly over-order serum lipids for the purposes of screening/monitoring – who here can honestly say they typically only order serum lipids at the the frequency of 5-yearly intervals? I love EBM but even that makes me feel anxious… Nonetheless, as ethical practitioners, the testing we recommend should be directed at maximising meaningful patient outcomes, and not at managing our therapeutic neuroses!

    • Hi Michael,

      You make a few very good points. On looking back at eTG 2013 guidelines for monitoring they are a little confused in their wording.

      “Liver and muscle biochemistry (alanine aminotransferase [ALT] and creatine kinase [CK]) should be tested at baseline and when the response of lipids is assessed (1 to 2 months after initiation or dosage adjustment).

      It is no longer considered necessary to routinely monitor liver biochemistry and CK unless the patient develops symptoms or signs of liver dysfunction or muscle problems. This avoids the problems associated with the detection of asymptomatic ALT or CK elevation, which are common findings. However, regular monitoring should be considered in patients taking combination lipid-modifying therapy.”

      Umm? Seems like the first sentence is slightly contradicted by the second?

      eTG quotes their reference as:
      “Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32(14):1769-818. [PubMed]”

      “Thompson PD, Clarkson PM, Rosenson RS. An assessment of statin safety by muscle experts. Am J Cardiol. 2006;97(8A):69C-76C. [PubMed]”

      On looking through them all I could find was:

      “The Muscle Expert Panel does not advocate routinely measuring or monitoring CK levels in asymptomatic patients because marked, clinically important CK elevations from statins alone are rare; most CK elevations during statin therapy are benign and related to such factors as recent physical exertion, and there is no evidence that the added cost of such monitoring improves medical care. 31”

      So not sure where this suggestion has come from? Consensus of opinion of Australian Experts? Either way I think I would still follow eTG guidelines for now as I think they are generally very reputable and reliable.

      They also don’t suggest complete withdrawal of the medication. They suggest either reduction in dose or stopping and reintroducing a different type or a fenofibrate.

      It’s interesting that ordering serum lipids at 5 yrly intervals makes you use the word ‘anxious’. Is this because this has been your practice for such a long time? Is it because you believe that their lipids might change rapidly if they are at low risk? It is an interesting statement that it makes you ‘anxious’. I’m guilty of this as well! I hear the evidence on something but for some reason am not always happy to go with it. We must have some reason for this, and maybe we should acknowledge it, in the same way we try to acknowledge counter-transference, and then reassess objectively? Tough call really! The ‘gut’ or the ‘guide’?

      Cheers, Rob.

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  6. Pingback: Comment: To statin or not to statin? | Michael Tam

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