Yes, if anyone is interested, I enjoyed my holiday. Mountains, snow, skiing, food, France. What more could you ask for?
Whilst away I kept an eyes on a whole series of stories on cholesterol and statins and adverse effects of statins, and suchlike, unfold across various newspapers. Many of you were kind enough to send me said various articles and stories. Some of which were easy to follow. One, in particular, was completely incomprehensible.
HOPE-3, was a study done by Astra Zeneca looking at the use of rosuvastatin vs. placebo. Actually, it was a study done using rosuvastatin alone vs. antihypertensive medication vs. rosuvastatin and antihypertensive medicine vs. double placebo (a term I have never come across before). Double placebo has twice the power of a single placebo? Yes, its ‘Double Placeboman’ playing at a cinema near you.
I have read the HOPE-3 article, and given up several times. I just cannot understand it. Professor Michel de Lorgeril (who ran the Lyon heart health study) also had a go at making it easier to understand. Below is part of his simplification which (I am afraid) is not terribly simple. But it may give you some gist. There is a prize for anyone who gets to his final point:
- No effect on all-cause mortality.
- No effect on cardiovascular mortality.
- As cardiovascular disease is a serial killer, we could conclude that rosuvastatin is shown useless in that trial (as in the previous trials). We could stop the analysis at this point.
- Since the authors do suggest that rosuvastatin was protective, it means that these patients are as “deaths cured”’ or “death prevented”, which is probably not what they expected when taking the pills.
- All this despite the LDL reduction that was close to 30%.
- HOPE 3 investigators curiously examine the effects of rosuvastatin on two “combined primary endpoints” (called “first and second co-primary outcome” as shown on Table 2, below) suggesting that there were two primary hypotheses. This is not “in line” with basic Methods in clinical trial sciences [one trial, one primary hypothesis]. That strange and novel strategy should have been presented long before starting the trial. In any case, the probability of a difference between rosuvastatin and placebo for the first co-primary outcome [the only one to be considered] should have been adapted, a kind of Bonferroni correction; p should have been much lower than 0.05 to be significant; which is not “clinical significance”.
- HOPE 3 investigators present the comparison of rosuvastatin with placebo (Table 2, below) as if there were only two randomized groups. In fact, there were 4 groups as there was a second randomization to test an antihypertensive treatment; and also the combination of cholesterol lowering and blood pressure lowering. In summary, these investigators tested many more than two primary hypotheses. They say that they can pool the data from all the patients taking rosuvastatin (plus antihypertensive) to make the comparison with all the patients taking a placebo, including those taking antihypertensive; thus comparing two groups of about 6300 patients rather than 4 groups of about 3100 patients each) because there was no interaction between treatments. This is not exactly true as we see a clear interaction between treatments for at least two components (myocardial infarction and stroke) of the two co-primary outcomes (see Table S20 in the supplementary materials, below). It would have been therefore imperative to present data and full statistics for the 4 groups together to examine the effects of rosuvastatin vs. placebo. It is a mistake not to do that. 6- HOPE 3 investigator also say that there were fewer heart attacks; but after almost 6 years and with about 13,000 patients randomized, there were only 114 heart attacks (45 vs 69 in a simplistic analysis of 2 groups only, Table 2 below).
- In fact, things are not so clear when looking at Table 2: they report for the first co-primary outcome (CV deaths + myocardial infarction + stroke) 304 events in the placebo group and 235 in the rosuvastatin group, thus numbers different from the sum of 171+69+99 (total 339, placebo group) Michel de Lorgeril 2016 and 154+45+70 (total 269, rosuvastatin) according to the numbers given in Table 2. This means that they do not use the same numbers in the Table and in the statistics. This is a way of misleading the readers.
Ahem. Perhaps not as simple as you may expect, but I hope you get the general drift. All I did, rather than Lorgeril, was attempt to pull out the figures of greatest interest, to me. Which should be the figures of greatest interest to everyone taking rosuvastatin. The absolute difference in number of deaths between those taking rosuvastatin and double placebo.
- After five years of treatment, in 3,181 people taking rosuvastatin, there were 171 deaths (of all causes)
- After five years of taking double strength placebo, in 3,168 people, there were 178 deaths (of all causes)
This represents a difference of 7 deaths over 15,905 years of treatment. Or, one death delayed for every 2,272 years of treatment. This is both statistically, and clinically, insignificant. It is well within the limits of a chance finding. It is a difference that can simply be ignored.
Of course, it was hailed as a triumph, and further proof of the cholesterol hypothesis.
Of more interest, in many ways, and coming out at almost exactly the same time as HOPE-3 was the ACCELERATE trial. Which looked at the use of evacetrapib on lowering LDL (‘bad’ cholesterol), and raising HDL (‘good cholesterol) on the risk of CVD. It was reported thus…
‘Cleveland Clinic researchers studying evacetrapib have shown that despite reducing levels of low-density lipoprotein (LDL, or “bad” cholesterol) by 37 percent and raising levels of high-density lipoprotein (HDL, or “good” cholesterol) by 130 percent, the drug failed to reduce rates of major cardiovascular events, including heart attack, stroke, angina or cardiovascular death.
The phase 3, multi-center clinical trial was discontinued in October 2015, on the recommendation of the independent Data Monitoring Committee after preliminary data suggested the study would not meet its primary endpoint of a reduction in major cardiovascular events. The research is being presented at the American College of Cardiology’s 65th Annual Scientific Session
“Here we have a paradox. The drug more than doubled HDL and lowered LDL levels by as much as many statins, but had no effect on cardiac events,” said Steve Nissen, M.D., chairman of Cardiovascular Medicine at Cleveland Clinic. “These findings illustrate the importance of performing large, high-quality outcome trials. Just looking at the effects a therapy has on cholesterol levels doesn’t always translate into clinical benefits.”
The ACCELERATE trial involved more than 12,000 patients at more than 540 sites who were at high risk for serious cardiovascular problems. They were randomized to receive either 130 milligrams of evacetrapib or a placebo daily, along with standard medical therapy throughout the trial. Study participants either had an acute coronary syndrome 30 days to one year before enrolling, had cerebrovascular atherosclerotic disease, had peripheral vascular disease, or had both diabetes and coronary artery disease.’
In HOPE3, LDL was lowered 30%, had some (very slight) impact on CVD, and was hailed as a triumph for cholesterol lowering. In ACCELERATE LDL was lowered 37%, HDL raised 130%, with no effect whatsoever on CVD. Aha, but, there is an answer…
The ACCELERATE trials was, you’ve guessed it. A paradox. [Question, how many paradoxes can a hypothesis sustain before it collapses in a smoking ruin?]
Karl Popper would call such a thing a black swan. Which is a refutation of your hypothesis. Karl Popper, as we all – ahem – know ‘proposed falsification as a solution to the problem of induction. Popper noticed that although a singular existential statement such as ‘there is a white swan’ cannot be used to affirm a universal statement, it can be used to show that one is false: the singular existential observation of a black swan serves to show that the universal statement ‘all swans are white’ is false—in logic this is called modus tollens. ‘There is a black swan’ implies ‘there is a non-white swan,’ which, in turn, implies ‘there is something that is a swan and that is not white’, hence ‘all swans are white’ is false, because that is the same as ‘there is nothing that is a swan and that is not white’.
One notices a white swan. From this one can conclude:
At least one swan is white.
From this, one may wish to conjecture:
All swans are white.
It is impractical to observe all the swans in the world to verify that they are all white.
Even so, the statement all swans are white is testable by being falsifiable. For, if in testing many swans, the researcher finds a single black swan, then the statement all swans are white would be falsified by the counterexample of the single black swan.’2
Here is another ‘white swan’ hypothesis
Researchers, looking at those living in Framingham, in the US, found that younger men with high cholesterol levels were more likely to die from CVD. From this they concluded. Raised cholesterol causes CVD. ACCELERATE clearly falsifies their simplistic hypothesis. It is a black swan. Thank you, and goodnight.
Next, part XII as to what causes heart disease.