#Cholesterol 5.8 mM, 224 mg/dl. Subtypes typical for such a total.

Non-smoker. Otherwise average.

[Live-quiz from #orbita-HQ for #cardioTwitter fellows & the curious]

First vote was for diet first, and quite right too! That is the guideline, and we must obey.

Natural, organic, eco-friendly and therefore best.

What effect size is a reasonable expectation, for patient and Dr, for the reduction of total cholesterol by diet?

(currently 0.8 mmol/L in the lead for Question C2)

There are several ways to choose a value. Which did you use?

I can also tease #ORBITA hq PhD students, who'll fall into same trap

Who was Archibald Cochrane?

A scientist who developed the warp drive?

A doctor who advocated randomized controlled trials?

A biologist who discovered statins?

A haematologist who developed a method of separating cholesterol into LDL, HDL and other bits

The "Cochrane Collaboration" is indeed a foundation providing syntheses of the best available evidence.

Here is there analysis on effect of diet on cholesterol.

onlinelibrary.wiley.com/doi/10.1002/14…

If in a hurry, skip to page 88, or search the PDF for "Analysis 1.5".

If you are actually riding a bike or balancing on a spike in a park, so have even less time, look at this pic.

The figure above is in mmol/l. Multiply by 40 to get mg/dl.

Based on the world total of careful RCTs, peer reviewed and reported by a variety of scientists that are not in collusion and *not* biased against diet, what is the typical effect size of diet on Chol?

Because I knew the answer to the following question (because I am so sad and lonely), and I realised the implications of the two facts.

Q C6

1000 men with 5.8 cholesterol (224) today have a recheck in a month. 950 of them will cover what range?

You might think that this would keep them bunched up.

But! clinchem.aaccjnls.org/content/clinch…

See pic

And the right-hand column, the variability, expressed as "coefficient of variation", which means SD divided by the mean value, written as a %.

Question C7.

From this, roughly what is the SD of repeated measurements?

Try and do without reading this.

Mean is 6 mM.

SD/Mean is about 5%.

SD must therefore be what?

Still stuck?

Got 20 friends.

You give each friend $30 of drinkies at your party. i.e. Total cost/nFriends=30.

How much party cost you?

Based on your calculated SD, what range do you expect 95% of values to lie in?

Remember, if a distribution is Normal [a future annoy-o-rama will examine what this means] about 95% of values lie within 1.96 SD of the mean. i.e. about mean-2SD to mean+2SD.

1000 men with 5.8 cholesterol (224) today, recheck in a month. 950 will cover what range?

Don't worry if you've changed your mind. (Even if you are an interventionist and never do so)

Thinking = changing ones mind.

So far, at ~10 votes, majority is right on Q7,8 and 9. So assume they are right. (#ORBITA-hq fellows - please SMS me if majority becomes wrong: "Brexit phenomenon")

Q10. Combine this with Cochrane value

Average effect of diet is what % of the "noise" SD?

DO NOT READ UNTIL YOU'VE TRIED.

Q7. option A.

Q8. option D.

Q9. option D.

Q10. option A.

If you can't see why, email me at d.francis@imperial.ac.uk and I will add an explanation later.

You'll need these answers for later.

Q C11. Our pt gets typical benefit seen in those carefully conducted, rigorously supervised trials (indeed @rallamee calls him daily and cooks his food out of kindness because he has a sad face)

What probability next chol HIGHER?

Dropping ON AVERAGE by 0.15 mM, but + a noise SD of 0.30 mM. If the noise is positive and >0.15 mM (half an SD) we will be screwed: the cholesterol will rise.

Add up the areas of the bars to the right of +0.5, in mathbits.com/MathBits/TISec…

Mean chol drop = -0.15

SD = 0.30

Click "above" and enter "0"

Question C12.

What is the probability that after a typically well-delivered diet, cholesterol will be *higher* than pre?

How can we prevent upsetting 30% of our pts who achieve RCT-level diet and yet, through *unavoidable* natural variability, find their next chol gone the wrong way?

Do patients understand biological variability well?

Do they know relative effect sizes of diet and statin?

If they find all of this difficult to cope with, what else can we do to help them achieve lower cholesterols?

It may be in contravention of guidelines, but I am ready to explain my reasoning along the above lines.

I am not against diet, I just don't want to set the patient up for a fall.

So statin from day 1, with diet, recheck only on both.

A sentence so ingeniously worded that, against all my baser instincts, I am forced to agree with @GreggWStone agreeing with you, as there is no logical way out of an NSTEMI being a STEMI without STE.

Let's put the 0.15mM (6 mg/dl) effects of diet into context. What effect size would you expect on average from (say) atorva 40mg, with starting cholesterol 5.8 mM (224 mg/dl)?

Here is a CURVES study graph (admittedly plotting LDL-cholesterol, not total cholesterol) showing effect sizes as a percentage of baseline.

Suppose the non-LDL cholesterol was about 2mM, so:

LDL was 3.8 mM (147 mg/dl)

ncbi.nlm.nih.gov/pubmed/9514454

Q C16.

Look at the graph above.

40mg of atorvastatin (solid round blobs) reduces LDL-C by what %?

Q C17.

We estimated our guy's LDL-C to be 3.8mM

So, based on the percentage you read off the graph, what will be the absolute (i.e. in mM, not %) fall in LDL-C?

Dan Keene ruined any interest I had in raising HDL: bmj.com/content/bmj/34…

"One agent for increasing HDL, torcetrapib, did significantly

change mortality, but [unfortunately] this was an increase."

So taking Dan's cue, let's cross our fingers and assume that HDL (and other things other than LDL) are unaffected.

Roughly what change will we expect in total cholesterol, therefore?

And so what is the approximate ratio between:

the effect size of 40mg of generic atorvastatin (UK price approx 5 US cents/day)

and

the effect size of a high-quality, RCT level supervision (@rallamee on speed dial) diet?

Perhaps you quantify CV risk and recommend statins to those at highest risk?

Or maybe you don't formally calculate risk in % over 10 years or whatever, but just mentally gauge it?

Q C20.

Initiating statins is most beneficial in:

Of course, it's so obvious we never question it.

But there is always a nasty sting in any of my questions that seem too easy, as you will by now have noticed. 🤓

Here the trap is that I didn't say what I meant by "most beneficial".

I am asking you to divide 1.9 mM by 0.15 mM.

I was hoping you could guess, e.g. is it going to be more or less than 10. But if you find that tricky, just use a calculator.

C21.

By "beneficial", which of these could I have meant?

Which of these quantities is most familiar to patients?

Think about whether the quantity is commonly talked about in general conversation.

Think what the unit of measurement is. Something tangible?

Depends on an arbitrary time window? Or covers all of time?

Everyone has heard of them; everyone wants them.

My friend Marianna Fontana, Cardiac MR guru at Royal Free, calculated life years gained from statins. circ.ahajournals.org/content/129/24…

Look at the plot carefully

ncbi.nlm.nih.gov/pmc/articles/P…

(Low res pic here)

Below is the more familiar SCORE chart of risk. It is part of our European guideline and on every UK Dr's desk in the "BNF" drugs book.

Compare.

Marianna's chart, of *life years gained from starting a statin* differs in only one way, other than having a less screamy colour scheme.

How does Marianna's LYG differ?

Both first responders are correct, thank you!

Of course Marianna's plot doesn't fail to do anything. It just reflects something that is obvious (in retrospect).

But not a big feature of guidelines.

Your STEMI patients go straight onto statins, yes?

Now think of your last 20 *primary prevention* statin initiations, instead. Remember the discussions about diet, lifestyle and meds?

Remember the to-and-fro?

Denial/anger/bargaining/acceptance?

What upset patients most?

So I argue that the major displeasure to patients of being on the statin is getting over that initial hurdle of trying the damn things.

Therefore the net benefit (utility minus disutility) is greatest at younger ages

but those at the bottom of the age spectrum.

Their large LYG comes from their youth.

Q C26