Just before I head off on holiday for a couple of weeks, I thought I should make a quick comment on the Repatha trial (PCSK9- inhibitor). I have written much about this new class of cholesterol lowering drugs, and I have been highly skeptical that they would have any benefits on cardiovascular disease. [Mainly on the basis that I don’t believe raised LDL causes CVD, and these drugs have one action – to lower LDL].
As many of you will be aware, the data from a clinical trial on Repatha has just been released. It was reported by the BBC thus
‘Huge advance’ in fighting world’s biggest killer.’
An innovative new drug can prevent heart attacks and strokes by cutting bad cholesterol to unprecedented levels, say doctors. The results of the large international trial on 27,000 patients means the drug could soon be used by millions.
The British Heart Foundation said the findings were a significant advance in fighting the biggest killer in the world. Around 15 million people die each year from heart attacks or stroke. Bad cholesterol is the villain in the heart world – it leads to blood vessels furring up, becoming easy to block which fatally starves the heart or brain of oxygen.
It is why millions of people take drugs called statins to reduce the amount of bad cholesterol . The new drug – evolocumab – changes the way the liver works to also cut bad cholesterol. “It is much more effective than statins,” said Prof Peter Sever, from Imperial College London.
He organised the bit of the trial taking place in the UK with funding from the drug company Amgen. Prof Sever told the BBC News website: “The end result was cholesterol levels came down and down and down and we’ve seen cholesterol levels lower than we have ever seen before in the practice of medicine.”
And so on, and so forth. So, the Repatha trial was a huge success. Obviously, it certainly lowered LDL to levels never seen before. Or, maybe it was not quite such a huge success. Michel de Logeril, a professor of cardiology in France – who set up and ran the famous, and successful, Lyon Heart Study sent me this comment.
‘This is just junk science.
The calculated follow-up duration required to test the primary hypothesis was 4 years as written by the authors themselves (but only in the second last paragraph before the end of discussion…) but the actual median duration of follow-up has been 2.2 years; it is thus a biased trial (a similar bias as in JUPITER: 1.9 years instead of 4 years): early stop!
In addition, contrary to the misleading claims in the medias, there was no effect on both total [444 deaths with evolocumab vs. 426 with placebo] and cardiovascular [251 vs. 240] mortality; which is not unexpected with a so short a follow-up.
They pretend that they are differences for non-fatal AMI and stroke but there is no difference in AMI and stroke mortality… Very strange… It would be critical to get access to the raw clinical data to verify the clinical history of each case in both groups.
Well, in my opinion and given the present state of consciousness among US doctors, FOURIER is a flop!
What he is saying, is that there was a reported reduction in non-fatal heart attacks and stroke. And less need for revascularization procedures e.g. PCI/stents. As you may gather Professor de Logeril would like to see the raw data to verify this. There is very little chance that this will be made available.
Anyway, that was the upside.
The downside is when you look at cardiovascular deaths.
- The total number of deaths from cardiovascular disease in the Repatha group was 251
- The total number of deaths from cardiovascular disease in the placebo group was 240
- So, 11 more people died of cardiovascular disease in the Repatha group
The overall mortality data
- The total number of, overall, deaths in the Repatha group was 444
- The total number of, overall, deaths in the placebo group was 426
- So, there were 18 more deaths in those taking Repatha.
The differences here are not large enough to be statistically significant. However, there were more, not less, deaths in the Repatha group, and more, not less, CV deaths. This study was also terminated early, which is extremely bad news for any clinical trial, and casts enormous doubt on any findings. It was supposed to last four years, but was stopped at 2.2 years. Why? Were the mortality curves heading rapidly in the wrong direction.
Alongside this, should be set the knowledge the Pfizer also had a PCSK9-inhibitor undergoing clinical trials, and they pulled the plug, right in the middle of it all.
Pfizer Ends Development Of Its PCSK9 Inhibitor
‘November 1, 2016 by Larry Husten
Immune issues and diminishing efficacy doomed the new drug.
Pfizer announced on Tuesday that it was discontinuing development of bococizumab, its cholesterol-lowering PCSK9 inhibitor under development.
“The totality of clinical information now available for bococizumab, taken together with the evolving treatment and market landscape for lipid-lowering agents, indicates that bococizumab is not likely to provide value to patients, physicians, or shareholders,” the company explained.
Pfizer said that it would halt two very large ongoing cardiovascular outcome studies with bococizumab, the 17,000 patient SPIRE 1 trial and the 10,000 patient SPIRE 2 trial. The trials were fully enrolled.’
Pulling the plug when 27,000 patients had been fully enrolled. What on earth did they see. Something more than slightly worrying. I guess we will never really know, but that is one hell of a write off.
It is also interesting to note that Amgen – the company selling Repatha, has announced that:
‘Amgen to refund cholesterol drug if patients suffer heart attack
Pledge aims to convince insurers to pay for $14,000-a-year medicine.’ 2
As reported in the Financial Times.
This is a big vote of confidence … not! I think, perhaps, we are looking at a doomed drug. Probably a doomed class of drugs. Has the cholesterol hypothesis been verified, or contradicted? I know I am biased, but I know what I think.