Wednesday, February 17, 2010

Cholesterol: Near miss in Edinburgh

Just another brief post. This group were very, very, very lucky. Crucifiction is supposed to be unpleasant.

What did they do? Well it was more of the usual stuff but, back in the early years of this century, it was still considered ethical to include a placebo group in a statin trial! Gasp, horror, call the ethics committee.

Anyway, 54 people, all with known heart disesae, were allowed to go for 24 months without the benefit of atrovastatin. You wouldn't do this in the states! But here in Scotland, well, a few more heart attacks and no one will notice.

So what does a greater than 50% reduction of LDL-C and a near 50% reduction in C reactive protein do for CAC score progression?

Diddley squat, as you would expect. It's all the usual quotes:

"statin treatment does not have a major effect on the rate of progression of coronary artery calcification"


"Serum low density lipoprotein concentrations were not correlated with the rate of progression of coronary calcification (r = 0.05, p = 0.62)"

All utterly tedious.

What grabbed me was the near miss. The CAC score progression in the atrovastatin group was not significantly different to the placebo group.

The p value was 0.18

What would have happened if the p had cracked the mystical p<0.05, say with bigger groups or longer follow up?

In this study atrovastatin "allowed" or "facilitated" progesssion by 26% per year, placebo by only 18% per year.

As I say, p=0.18

A near miss for the careers of all involved.


Oh, and in the full text you can find that there were actually 2 diabetic patients and 10 current smokers in the placebo group vs no diabetics and only 5 current smokers in the statin group. Equalising these might have given catastrophe.


Chris said...

it is all happening in Scotland at the moment:

Peter said...


"However, the potentially raised diabetes risk should be taken into account if statin therapy is considered for patients at low cardiovascular risk or patient groups in which cardiovascular benefit has not been proven."

Once you look at all cause mortality that's all women and all men except men between 30 and 50 who have already had a heart attack then? Glad my pension is not dependent on simvastatin sales...

Also in Scotland we have finally halted the fall in CV deaths amongst the poorest folks in Maryhill and the like. Quite an achievement when CV deaths have been falling since the 1950's...


Ned Kock said...

I have actually caught a doctoral student (in a different field) REDUCING a sample size (by selectively deleting cases) to get a higher P value and avoid having to admit to an “odd” significant effect.

I am not saying that this is what happened here, of course …

Previously I thought that sample size cheating was usually done by increasing it through copy-and-paste fabrication; which is easy to catch anyway. No anymore.

Peter said...

Hi Ned,

I'd heard that fabricated data were relatively easy to detect and people have to be more subtle nowadays. Years ago Jennifer Hunter, then editor of the British Journal of Anaesthesia, gave us a vet anaesthetists a presentation about fraud in anaesthesia research. In the late 1990s it was running at about 10% detectable in BJA submissions.

Massaging your results, when you "know" the correct answer, must be very tempting... Of course I'd not really thought they had done this. But no one would want that low p value here...


donny said...

"Statins have been extremely successful in the primary and secondary prevention of cardiovascular disease. Why then have we and others not observed a beneficial effect of statin on coronary artery calcification? Unstable atherosclerotic plaques have a large lipid‐rich core, a preponderance of macrophages and foam cells, and a thin fibrous cap containing few smooth muscle cells.24 It has been suggested that calcified lesions may be relatively more stable,25 indicating a possible protective role of calcification in coronary plaques. Statins produce many of their beneficial effects through plaque stabilisation. In both primate26 and swine27 models, antiatherosclerotic interventions are associated with an increase in vascular fibrous tissue and calcification. This calcium deposition continues during the initial phase of plaque regression due to the death of foam cells and an increase in necrotic tissue. Thus, vascular calcification may have a role in the initial stabilisation of atherosclerotic plaques. This is consistent with our findings and would account for the lack of effect on the progression of coronary artery calcification despite a reduction in serum CRP concentrations."

Of course, if you accept this explanation, you're stuck with just waiting around to see if people start dying or not.

"Why then have we and others not observed a beneficial effect of statin on coronary artery calcification?" Why the use of the word beneficial? They go on to say that they would not have been able to tell whether a significant reversal of calcification would have been beneficial or not. Would they have mentioned the primates and the swine, if the statin had caused a dramatic reversal of calcium?

Peter said...

Donny, I have no doubt that calcium is an adaptive strengthening of weakened arteries. I have a nice photomicrograph to show this for some time in the next few posts. The calcium doesn't regress with statins because statins do nothing to stop the damage that arteriosclerosis is the follow on from...

It is very clear that statins decrease soft end points. Anyone in a statin trial going to their doctor with indigestion is going to get a stent put in. Ditto for mild chest pain. For minor cardiac pain it looks like statins vasodilate arteries through enhanced NO release. Less chest pain, less soft end points like procedures. Hard end points like cardiovacular death don't go down, not even in JUPITER... (exception is 4S, but we all know about the 4S data set)


Dr. William Davis said...

Hi, Peter--

Your discussion was cited in our Track Your Plaque Forum. Great post.

It highlights the fact that there's more to coronary disease causation than the effects exerted by statin drugs. (Duh!!) Just addressing vitamin D alone exerts substantial benefits on progression of coronary calcification.

There's more to the world than statin drugs. Keep up the good work.

Peter said...

Thanks Dr Davis,

I have this basic tenet that the world has to be understandable......