While studies occasionally reach incorrect conclusions, researchers can assist in correcting the record.
Photo by Pietro JengWhen it comes to clinical research, randomised, double-blind, placebo-controlled trials are the most effective sort of study.
But even a well-designed experiment can provide questionable results. A recent follow-up on a 2019 cardiovascular study termed REDUCE-IT is an excellent illustration of a lesson that can be learned. While novel medicines are the focus of many clinical trials such as this one, the selection of the placebo is equally crucial.
What made this study so compelling?
In this type of study, people are randomly put into one of two groups: the treatment being tested (like a new medicine) or a fake treatment (called a "placebo").
Neither study participants nor researchers are aware of who is receiving the active medication versus the placebo. In other words, they are both blind to group assignment, hence the term "double-blind. The treatment assignment is coded and kept secret until the end of the trial, or it is decoded at set times to check on the effectiveness or safety of the treatment.
This decreases the likelihood that researcher or participant expectations may influence study outcomes. This implies that any changes in health or side effects can be traced to the treatment—or lack thereof.
What you need to know about placebo treatment
Participants and researchers should not be able to distinguish between an active treatment and a placebo. Occasionally, though, individuals may be able to identify what they received. For instance, the active medication may have an unpleasant taste or an obvious adverse effect like diarrhoea.
The trial is no longer double-blind if this occurs. This suggests that expectations may influence outcomes. During or after a trial, researchers can test this by asking participants whether they believed they were receiving an active treatment or a placebo. If the responses appear random or if the participants respond with "I don't know," then blinding was successful.
Although a placebo should have no impact, this is not often the case.
The well-known placebo effect is a positive impact associated with an anticipation of benefit: if you tell someone that a pill can alleviate pain, some individuals will experience pain relief even though the medication is inactive.
The nocebo effect is a negative side effect caused by a placebo: if you inform someone that the placebo pill they are taking may induce diarrhoea, the expectation may cause some people to suffer diarrhoea. (The exact same placebo used in another trial may cause headaches if the individual is told of this side effect.)
REDUCE-IT highlights the significance of selecting a placebo with care.
REDUCE-IT is officially known as the Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial. The goal of the study was to find out if the drug icosapent ethyl could lower triglyceride levels to prevent heart attacks, strokes, and other cardiovascular diseases.
Triglycerides are a type of blood lipid. High triglycerides may increase the risk of heart disease, but doctors aren't sure if treatments that lower triglycerides prevent heart attacks and strokes.
Triglyceride levels were reduced in subjects who were administered the active medication. Cardiovascular disorders like heart attack and stroke were reduced by a whopping 25% when compared to the placebo group. Even cardiovascular mortality was reduced by 20% in the therapy group.
Based on these facts, the FDA approved a drug label that said icosapent ethyl was good for people with heart disease who were at high risk.
But shortly after the 2019 study was published, doubts arose. The therapy group performed better than the placebo group, which is correct. But a close look at the results showed that this might have been because people in the placebo group had more heart attacks and strokes over time, not because people in the treatment group had less.
A subsequent investigation reveals a different outcome.
In response to these questions, the authors of the study conducted additional analyses. This time, the researchers examined blood biomarkers related to cardiovascular risk. The biomarker results of participants receiving the active medication showed little variation. But biomarkers got worse in the placebo group, which suggests that the apparent benefit of the medicine may have been caused by the bad effects of the placebo!
How may a placebo increase the risk of cardiovascular disease?
One hypothesis is that the mineral oil placebo used in this study inhibited the absorption of cholesterol-lowering statin medications, which can influence heart and blood vessel health. Still, this new analysis shows that people were right to be sceptical about the shocking results of the first study and that more research is needed.
The conclusion
For me, there are three takeaways from this story:
There are numerous ways for research to come to erroneous conclusions; a poor placebo choice is uncommon, but it appears to be the case here.
For medical research to be taken seriously, researchers must be willing to take criticism, re-evaluate their findings, and, if necessary, do more research.
In the case of REDUCE-IT, it appears that this self-correcting procedure was successful.
After the inaugural investigation of icosapent ethyl in 2019, there was considerable interest in the medicine. In light of this current analysis, though, this enthusiasm is likely to diminish. However, one thing should be made clear: science is not indecisive, as is commonly said. Revaluation and correction, when necessary, is how science is intended to function.
A placebo should have no direct biological effects on the individual receiving it. And it appears that this is where REDUCE-IT went wrong.
