17th February 2019
To an extent I am cursing myself for doing what I am about to do. I’ve been dragged, yet again, into reviewing a paper which has made headlines around the world which proved, yes demonstrated , that adherence to statins saves lives. I am doing this review because a lot of folks have asked for my opinion on the paper.
I do feel like saying. ‘Look, I wrote the book Doctoring Data so that you could read newspapers like this and work out why they are complete nonsense for yourselves’. Clearly, not enough people have read my book, and I’d therefore heartily encourage another million or so people to do so. [Conflict of Interest statement — I will get lots of money if this happens, which I think of as”win, win”].
The paper, in this case was known as’Association of statin adherence with mortality in patients with atherosclerotic cardiovascular disease.’ It was printed in the New England Journal of Medicine (NEJM) a few days ago.
The primary finding was:
‘With a national sample of Veterans Affairs patients with ASCVD (atherosclerotic cardiovascular disease), we found a low adherence to statin treatment was associated with a greater risk of dying. Women, minorities, younger adults, and older adults were less likely to adhere to statins. Our findings underscore the importance of finding approaches to improve adherence.’
First thing to say is that this was an observational study. So, it can’t be used to prove causality, particularly as the improvement in outcomes that they observed was an increased mortality risk of 1.3 (HR) in people who were least adherent — compared to those who were adherent.
As lots of folks know… sorry I will rephrase that… as many geeks like myself understand, if the hazard ratio is less than two, in an observational study, the best thing to do with said paper is to crumple it up and throw it in the bin. Because it’s almost certainly meaningless. To quote Sir Richard Doll and Richard Peto, two of the fathers of medical research and epidemiology:
“when relative risk lies between 1 and 2… problems of interpretation may become severe, and it could be extremely hard to disentangle the various contributions of biased data, confounding of two or more factors, and cause and effect.” 2
Observational studies with relative risks between one and two, are the type of studies that find that drinking five cups of coffee protect against CVD – or might be raise the risk of dying of CVD. Or maybe it’s tea, not coffee? [I apologise for mixing up odds ratios, hazard ratios and relative risk. For ease of understanding, consider these as the same thing].
For example, I was looking at this paper:
‘Tea and coffee consumption and cardiovascular morbidity and mortality‘.
Where they found that drinking between three and six cups of coffee reduced CV mortality by 45%:
‘A U-shaped association between tea and CHD mortality has been observed, with an HR of 0.55 for 3.1 to 6.0 cups per day.’ 3
That is a far better result than adhering to statins. After all it’s a 45% reduction vs. 30% reduction. My advice therefore would be to stop the statins and have nice cup of tea instead. Life would be so much better, and you’d live longer too. Sorry, but I do not know what type of tea. So many stupid studies to read. So much crumpling.
Leaving behind the nonsenses they are – the observational studies with a second difference in hazard ratio – let us move on to the major confounder of the latest crumple, bin, paper. Which is that those who adhere to medications do far better than those who do not — even if that medication is a placebo.
This was first noted, concerning cholesterol lowering medications, nearly forty years back in another paper, coincidentally published in the NEJM.
Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project.
I’ve copied the abstract in full. In part because it is written in something similar to clear English. Most unusual in any medical journal. In this study the researchers were looking at drugs used to lower cholesterol levels, before the invasion of the statins.
‘The Coronary Drug Project was carried out to assess the efficacy and safety of several lipid-influencing drugs in the long-term treatment of coronary heart disease. Good adherers to clofibrate, i.e., patients who took 80 per cent or more of the routine prescription throughout the five-year follow-up interval, had a substantially lower five-year mortality than did poor adherers to clofibrate (15.0 vs. 24.6 percent; P = 0.00011).
However, similar findings were noted in the placebo group, i.e., 15.1 per cent mortality for good adherers and 28.3 percent for poor adherers (P = 4.7×10-16). These findings and various other analyses of mortality in the clofibrate and placebo groups of this project show the serious difficulty, if not impossibility, of evaluating treatment efficacy in subgroups determined by patient responses (e.g., adherence or cholesterol change) into the treatment protocol following randomization.’
I think it is worth highlighting the main findings again.
Those who adhered to taking clofibrate = 15% mortality
People who had poor adherence to clofibrate = 24.6percent mortality
Those who adhered to taking placebo = 15.1percent mortality
Those who had poor adherence to placebo = 28.3percent mortality
From this is can be established that it was worse that you not take placebo regularly than it was to not take clofibrate regularly.
If we proceed in time, others have looked at adherence to taking statins. The first thing they noticed was people who take their medication regularly are different in many, many, ways to people who have poor adherence.
The paper is called: ‘Statin adherence and risk of injuries, a cautionary tale.’ Published in the American Heart Association journal Circulation.
‘Bias in studies of preventive drugs can occur when healthy patients are more likely to initiate and adhere to therapy than less healthy patients. We sought evidence of this bias by examining associations between statin exposure and various results that shouldn’t be causally affected by statin exposure, such as workplace and motor vehicle accidents.’
‘Our study contributes compelling evidence that individuals who adhere to statins are systematically more health seeking than comparable patients who do not remain adherent. Caution is warranted when interpreting analyses that feature surprising protective effects to preventive medications.’
“when relative risk lies between 1 and 2… problems of interpretation may become severe, and it may be extremely difficult to disentangle the various contributions of biased data, confounding of two or more variables, and cause and effect”
In the case of this latest’nonsense’ paper on statins, it isn’t actually hard to disentangle the various contributions of biased information.
We already know that people who take tablets regularly, and placebo frequently, are more health looking than those who don’t. We already know that if you take a placebo regularly, this almost halves your (complete ) mortality rate. These are both enormous confounders from the latest NEJM study.
In fact, the confounder effect unearthed in previous studies is much bigger than the effect they found. Which, if you will be logical, would suggest you would be far better off regularly taking a placebo than frequently taking a statin. If you decide to do this, you could entitle their newspaper”Proof that statins have no beneficial effect”.
You sure as hell cannot use such data to indicate that adhering to statins is beneficial. Yet, the authors of this study have done so. I provide their paper a sign of D-Fail, please try again.
If not, I’d say, please inform yourselves of the previous research done in this area before writing a paper. This will avoid wasting everyone’s valuable time.
2: Richard Doll & Richard Peto, The Causes of Cancer 1219 (Oxford Univ.. Press 1981).