This episode takes a deep dive into the evidence for and against the lipid hypothesis. The lipid hypothesis states that abnormal blood cholesterol levels cause cardiovascular disease. But is this true? Does high LDL (“bad cholesterol”) and/or low HDL (“good cholesterol”) actually CAUSE cardiovascular disease or is it just an association? This episode was recorded live from a General Practitioner conference. To view the presentation with the slideshow visit: www.youtube.com/DrDanMD
There’s a new cholesterol lowering drug in town and its ability to lower cholesterol is like nothing we’ve ever seen before. It’s called Evolocumab, (trade name Repatha) but is it any good at reducing cardiovascular disease? This week, we delve into the FOURIER trial – a humongous randomised controlled trial that will answer this question.
Development of Evolocumab
Evolocumab is a monoclonal antibody PCSK9 inhibitor. It’s actually an interesting story how this drug came to be. A group in Paris who do a lot of research on families with familial hypercholesterolemia had long known about a mutation on Chromosome 1 that was associated with some of these families. They had no idea where and what the gene did but they were aware of it. Then, in another part of the world, researchers in Canada had discovered a new protein involved in cholesterol regulation whose gene was also located on Chromosome 1. The two teams got together and eventually, in 2003, discovered it was all the same gene. The gene was for PCSK9 and certain mutations that over-activated this gene seemed to be linked to familial hypercholesterolemia. But it was also discovered that people with mutations that de-activated this gene had very low levels of cholesterol and perhaps even reduced cardiovascular disease. The more PCSK9 the higher your cholesterol and the less PCSK9 the lower your cholesterol. So what if we could block PSK9? Well, this multi billion dollar idea was quickly developed by Amgen who made Evolocumab – a fully human monoclonal antibody that binds to PCSK9 and inhibits it. Early phase clinical trials have shown that its ability to reduce LDL is out of this world, like nothing we’ve ever seen before. but we’ve been waiting for big trials on whether it has any impact on cardiovascular disease.
Wait no longer! Because the FOURIER trial has arrived. It stands for Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk. …..bit of a stretch if you ask me.
This trial was published in the NEJM in March of 2017.
They recruited 27,564 patients from 49 countries between he ages of 40 and 85 with cardiovascular disease. They had to either have had a stroke, a heart attack or symptomatic peripheral vascular disease. People with angina or stents were not considered having cardiovascular disease.
The patients also had to have other risk factors that put them at even higher risk than your average secondary prevention patient, like diabetes or smoking.
They had to have at least an LDL of 1.8mmol/L (70mg/dL) and they had to already be on a statin.
They were then randomised to either evolocumab or placebo injections. If they were randomised to the evolocumab group, then they could choose between having a 140mg injection every 2 weeks or 420mg injections every month. And the gave the same choice to those in the placebo group to ensure blinding.
They ended up with 27,564 patients. The average age was 63 and one-quarter of them were women. 80% of them had had a history of myocardial infarction and 20% had a history of stroke. 70% were taking a high dose statin and the rest were taking a moderate dose. 90% were on aspirin. 30% of them were smokers….even after having their heart attack or stroke!
The average LDL was 2.4mmol/L (92mg/dL), and they were able to lower this by 60% with evolocumab….which is huge! Most were already on maximal dose statin so this is very impressive.
They followed them up for just over 2 years.
The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization.
So what did they find?
The primary outcome occurred in 11.3% of the placebo group, and in the evolocumab group…it went down to 9.8%. So this gives a 1.5% absolute reduction. The relative risk reduction is 13%
Where relative risk reduction is very useful is if the baseline risk is different for everyone. So in this study, it showed that evolocumab had an absolute risk reduction of 1.5%….but that’s only if your baseline risk is 11.3% over 2 years. If your baseline risk is 5% over 2 years, then this number is no longer true. And this is where relative risk is useful. Because we can apply it to people’s baseline risk to determine their individual absolute risk reduction. Using the relative risk reduction of 13%, if our patient has a 5-year cardiovascular risk of 10%, then giving evolocumab for 5 years will reduce that by 13% to 8.7% – making an absolute risk reduction of 1.3% for that patient. But if our patient has a 5-year risk of 3%, then evolocumab will only reduce it down to 2.6% – making an absolute risk reduction of 0.4%.
Relative risk is also good when comparing it to other drugs. Compare Evolocumab’s 13% relative risk reduction to high dose statins which reduce risk by 35%!. Or to ezetimibe which reduces risk by 6%. Or antihypertensives which reduce risk by about 25%. So hopefully that puts evolocumab in perspective.
Now, it’s important to see exactly where this 13% risk reduction came from. Because it was a 13% reduction in any of heart attacks, strokes, unstable angina or revascularization, and I think we can all agree that a 13% reduction in risk of revascularization or angina is very different to a 13% reduction in cardiovascular death.
So firstly, there was absolutely no reduction in death – cardiovascular death or death from any cause. Not even a signal of benefit there – it was 3.1% in the placebo group and 3.2% in the evolocumab group. There was a reduction in non-fatal myocardial infarction, this went from 4.6% down to 3.4%, and stroke also went down from 1.9 to 1.5
In terms of harms – they could not find any difference. And they looked at a lot: cognitive impairment, muscle aches, bleeding, allergic reactions. There was a slight increase in injection site reactions but this was rare.
- Sponsorship: The manufacturer of the drug sponsored the trial – they were involved in designing the trial and collecting the data. They then gave the raw database with all the data to an independent group called the TIMI group and they were responsible for analysing the data. So industry was involved but this trial would never have happened and probably wouldn’t have been as robust if not for industry funding.
- Lipid Hypothesis: This trial and the positive results of the trial, has re-opened this whole debate about the lipid hypothesis. This is the debate as to whether lowering cholesterol is important – no matter which drug…or whether the drug is important and it doesn’t matter what it does to cholesterol. There is probably no bigger debate in evidence based medicine than this. A lot of proponents for the lipid hypothesis consider this trial a great victory to their belief system but I wouldn’t be so quick to jump on the band wagon because there are a few holes to the theory in this trial. Firstly, the investigators divided the patients in this trial based on their starting LDL. In the lipid hypothesis, we would expect a greater benefit from reducing cholesterol in those who have a very high cholesterol – The higher the cholesterol the greater the risk and so the greater the reduction in cardiovascular disease with treating such high cholesterol. We see this in hypertension, reducing blood pressure from 180 systolic with an antihypertensive gives you a much greater benefit than reducing a 140 systolic with that same antihypertensive. But this was not seen…there was the exact same benefit if your starting LDL was 3.4mmol/L or if it was 1.8mmol/L. Secondly, there’s a group called the cholesterol trialists who did a big meta-analysis of cholesterol lowering in 2012, and their conclusion was that it doesn’t matter what you use to lower cholesterol, every 1mmol/L reduction in LDL will result in a 23% relative reduction in cardiovascular events over 5 years. This trial showed that evolocumab reduced LDL by 1.6mmol/L – so if we apply this rule of the clinical trialists, this should equate to a 37% reduction in cardiovascular disease. But it didn’t – It led to a 13% reduction in cardiovascular disease. So clearly the impact of cholesterol lowering is not consistent across the different drugs.
- Another point to mention is that these were not your average secondary prevention patients. It’s very common for a drug to be released onto the market with a very narrow indication but this tends to expand over time. It’s difficult to say whether this medication will benefit your average secondary prevention case. After all, not only had these patients already had a heart attack or a stroke, but they also had risk factors on top of that like smoking or diabetes. Even worse, my fear is that this drug will creep into the primary prevention space even though it’s very doubtful it has any meaningful effects in primary prevention.,
- Cost: Evolocumab currently costs 14,300 USD per year of treatment. So let’s make a calculation. This study showed a number needed to treat of 67 over 2.2 years. So if you multiply 14,300 by 2.2 and then by 67 – this drug costs 2.1 million dollars to avoid one non-fatal heart attack or non-fatal stroke. That will not save any lives, just reduce a heart attack….for 2.1 million dollars. Can you imagine how many heart attacks you would avoid by putting 2.1 million dollars into exercise programs? Currently, the Government in Australia will pay for the medication in those with homozygous familial hypercholesterolaemia.
We now have 3 medications that lower cholesterol and reduce cardiovascular disease. The latest is the monoclonal antibody, Evolocumab (Repatha), which is able to reduce cardiovascular disease by a relative reduction of 13%. Compare this to high dose statins which reduce cardiovascular disease by 35% and ezetimibe which reduces CVD by 6% (relative). Evolocumab does not reduce death. It currently costs 14,000 US dollars per year, which equates to 2 million dollars per nonfatal heart attack avoided.
References & Links:
- Dr. Dan Videos: www.youtube.com/drdanmd
- FOURIER trial: http://www.nejm.org/doi/full/10.1056/NEJMoa1615664