By Marika Sboros
Are cholesterol-lowering drugs known as statins really just victims of vested interests’ propaganda?
In the Lancet, UK researchers say that most people imagine the negative side-effects of statins. Co-authors are Prof Peter Sever, of Imperial College, London and Prof Sir Rory Collins of Oxford University.
Scottish GP Dr Malcom Kendrick sees things differently. Kendrick has a special interest in cardiovascular disease. In his latest blog post, he takes what he calls a ‘pretty forensic look’ at the Lancet study. From a scientific perspective, it is anything but pretty.
Kendrick is one of my favourite sources of perspective on scientific controversies to do with heart health. He is author of The Great Cholesterol Con: The Truth About What Causes Heart Disease And How To Avoid It. He is also author of Doctoring Data, How To Sort Out Medical Advice From Medical Nonsense.
Of the new Lancet study, Kendrick says that he has found ‘a weakness – or two – or three – or … you get the picture’. Here is his assessment of it:
By Malcolm Kendrick
I have been somewhat silent over the last two or three weeks on this blog. The word ‘swamped’ springs to mind. The main swamping thing (alongside work and suchlike) that I have been doing is to analyse the Lancet paper which claimed that, basically, statins cause no adverse events.
Prof Peter Sever (corresponding author), followed up the publication of this paper with statements such as:
‘While statins do have some potentially serious side effects, including a slightly raised risk of developing type II diabetes and, very rarely, a potentially fatal muscle condition known as rhabdomyolysis, Sever said that the Medicines and Healthcare Products Regulatory Agency (MHRA) should remove warnings of side-effects including muscle pain and weakness, sleep disturbance, erectile dysfunction and problems with cognitive function.’
A real ‘tragedy’?
In an interview with UK national newspaper, The Daily Telegraph, Sever went on to say that:There are people out there who are dying because they’re not taking statins.
‘And the numbers are large, the numbers are tens of thousands, if not hundreds of thousands.
He said that it was a ‘tragedy’ akin to the MMR scandal that high-risk patients had been deterred from taking drugs which could save their lives.
Urging patients not to ‘gamble’ with the risk of heart attacks and strokes, he said ‘bad science’ had misled the public, deterring many from taking life-saving medication
And so on and so forth. As you may expect, his paper has been picked up by the mainstream medical media and other doctors with great enthusiasm.
Where does truth lie?
Here is a Dr John Mandrola writing a commentary in Medscape.
‘The frequency of muscle symptoms with statins is hotly debated. Randomized controlled trials (RCTs) in which patients don’t know whether they are taking the statin or a placebo report nearly identical rates of muscle-related adverse events. Observational studies, however, report higher rates of statin muscle complaints.
‘As a practicing doctor, I have always felt the truth lies closer to the observational data. A study published recently in the Lancet suggests I may be wrong. This new study, which has impeccable methods, suggests statin muscle complaints stem not from human muscles but from the human brain. In the Lancet paper, researchers took advantage of two distinct parts of the primary prevention ASCOT-LLA trial.
Click here to read: Statins insanity: Sir Collins of Statinshire at helm
‘In the first part of ASCOT-LLA, more than 10,000 people were randomized to either atorvastatin 10 mg daily or placebo in a double-blinded fashion. After completion of the blinded phase of ASCOT-LLA, study participants were invited to take part in a non-blinded and non-randomized extension study in which they could take atorvastatin open label.
Results ‘hard to dispute’?
‘The results turned on whether people knew they were on the statin. In the double-blinded phase of the trial, muscle symptoms occurred at the same rate—2.0% per year in both the statin and placebo groups. In the second phase of the trial, when people knew they were on the statin, side effects occurred at a higher rate (1.3% per year) in the statin group vs the placebo group (1.0% per year). This difference reached statistical significance (hazard ratio 1.41, CI 1.10–1.79; P=0.006).
‘These are remarkable observations, which are hard to dispute. In an accompanying editorial, two Spanish authors emphasized the obvious strengths of this paper: these were the same patients in both phases, and there was no run-in period in which patients intolerant to statins were excluded.’
So, this is a slam dunk. Right?
Well, I have taken a pretty forensic look at the Lancet Paper. It has the snappy title: Adverse events associated with unblinded, but not with blinded, statin therapy in the Angle-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA); a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase.
Getting facts right
It may not surprise you to know that Professor Sir Rory Collins was a co-author. I believe it may have a weakness – or two – or three – or … you get the picture.
However, if you are going to attempt to argue against such a paper, or pick holes in it, you need to study it with extreme care. You must make sure that you have your facts absolutely right.
Then, you need to look at all other associated papers around the entire ASCOT study. For example, I have amused myself, or not, by studying ‘Rationale, design, methods and baseline demography of participants in the Anglo-Scandinavian Cardiac Outcomes Trial’…. And a few other papers as well.
I have also been speaking to some very bright people who understand exactly how clinical studies are done, how adverse events are reported and recorded. It is an arcane and opaque world indeed.
You need to try to understand comments such as this, in the paper:
‘After randomisation, study participants were scheduled to be seen at 6 weeks and 3 months and then at 6 monthly intervals thereafter during both the blinding randomised and non-blinding randomised phases of the ASCOT-LLA (until the ASCOT-BPLA completed – (yes this was two trials in one). At each study visit, all adverse events (AEs) reported by participants were recorded by the study team in the case report form. Specific questions relating to any putative AEs were not asked at these visits.
Reports of AEs by the study participants were initially recorded verbatim and subsequently classified with use of the Medical Dictionary for Regulatory Activities into 26 separate system organ class (SOC) groups, 2288 unique preferred terms, and 5109 separated low-level terms…..’
Click here to read: Don’t swallow what doctors say on statins
Where’s the sense?
Now, I defy anyone to make sense of that. (I had no idea what the word putative meant in this context. Having looked it up, I am none the wiser.) Either the researchers recorded adverse reports were initially onto a case report form, or recorded comments verbatim and subsequently classified them. You can do one, or the other, not both. However, as for attempting to reclassify verbatim reports, in several different languages, 15 years later….
However, whilst trying to get my head around that, those involved in this data analysis piqued by interest. It turns out that the lead author, Ajay Gupta, was provided with financial support from the ‘Foundation for Circulatory Health’. I had never heard of this ‘charity’ before. So I tried to find out how it was funded – always tricky. You can usually find out who provides the dosh, but not how much.
Looking at their accounts, the Foundation for Circulatory Health seems to be funded largely (almost entirely?) by the pharmaceutical industry. Companies which include, guess who, Pfizer, who funded the initial ASCOT study and who also funded the recent Lancet Nocebo paper.
- Boston Scientific
- Patients attending Hypertension and Cardiology Clinics
Digging further it then turned out that Peter Sever and Neil Poulter (key authors on the ‘nocebo’ paper) are also directors of the Foundation for Circulatory Health, which funded Dr Gupta to work on the Nocebo paper – and which Pfizer supported.
Well, who’d a thunk? (Well, me actually.)
Neil Poulter is a very well-known researcher in CV medicine, well known to those who keep track of such things. His name turns up all over the place. Here was his declaration of interest statement in the Lancet paper:
‘Neil Poulter’s institution (Imperial College London) held a grant for the conduct of the Anglo-Scandinavian Cardiac Outcomes Trial in the UK and Ireland and he has also received a speaker’s honoraria from Pfizer outside the submitted work. He is also a recipient of the National Institute for Health Research Senior Investigator Award to Imperial College Healthcare NHS Trust.’
Sounds quite reasonable(ish) and above board. However, compare this with a conflict of interest statement from 2008: ‘Poulter disclosed receiving ad hoc payments to appear on advisory boards/deliver lectures for “all the major pharmaceutical companies that produce major agents in hypertension and CV medicine” and receiving grant income from Pfizer and Servier’.
Perhaps he just forgot that he had received money from all the major pharmaceutical companies that produce major agents in hypertension and CV medicine. Must be hard to keep track of what you have previously disclosed. Is there a time limit on conflicts of interest?
For now, I shall continue to dig. I shall continue to analyse the paper. Watch this space. It is all rather time-consuming, but it may turn out rather well in the end. Although I suppose that rather depends on which side you are on in this debate.