The case of the bad placebo

When it comes to clinical research, the most powerful type of study is a randomized, double-blind, placebo-controlled trial.

But even a well-designed trial can arrive at questionable conclusions. A recent follow-up on a 2019 cardiovascular study dubbed REDUCE-IT is one example that offers a great lesson. While innovative treatments are the focus of many clinical trials like this one, the choice of placebo is critical as well.

What made this a powerful study?

In this type of study, subjects are randomly assigned to two groups: one group receives the treatment being evaluated (such as a new drug) while the other group gets a fake treatment called a placebo.

Neither study subjects nor researchers know who is receiving active treatment and who is receiving placebo. That is, they are both blind to group assignment — that’s why it’s called double-blind. Treatment assignment is coded and kept secret until the end of the study, or decoded at earlier, planned intervals to monitor effectiveness or safety.

This reduces the chance that expectations of the researchers or participants will bias study outcomes. That means any differences in health or side effects can reasonably be attributed to the treatment — or lack of it.

What to know about placebo treatment

Ideally, study participants and researchers cannot tell who is getting an active treatment and who is getting a placebo. But sometimes, participants might be able to tell what they received. For example, the active treatment might have a bitter taste, or a noticeable side effect such as diarrhea.

If that happens, the study is no longer double-blind. This means expectations could affect outcomes. Studies can assess this by asking participants during or after the trial whether they thought they were taking an active treatment or a placebo. If the answers seem random or the subjects answer “I don’t know,” blinding was successful.

While a placebo treatment should have no effect, that’s not always true:

  • The well-known placebo effect is a positive effect related to an expectation of benefit: if you tell someone a pill can relieve pain, some people will experience pain relief, even if that pill was a placebo.
  • A negative side effect due to a placebo is called the nocebo effect: if you tell someone they might develop diarrhea from the placebo pill they’re taking, the expectation may cause some people to experience this. (The very same placebo used in another study may trigger headaches if that’s the side effect the study subject is warned about.)

Finally, a placebo should not have any direct, biological impact on the person taking it. And that seems to be where REDUCE-IT went wrong.

REDUCE-IT demonstrates the importance of choosing a placebo carefully

The full name of REDUCE-IT is the Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial). It was designed to determine whether the drug icosapent ethyl could lower triglyceride levels as a way to reduce cardiovascular disease, such as heart attack or stroke.

Triglycerides are a type of fat in the blood. High levels may increase cardiovascular risk, but experts aren’t sure whether treatments to lower triglyceride levels result in fewer heart attacks or strokes.

Among participants who received the active drug, triglyceride levels fell. Rates of cardiovascular problems, including heart attack or stroke, were a whopping 25% lower compared with rates in those assigned to take a placebo. There was even a 20% reduction in cardiovascular deaths in the treatment group.

Based on these findings, the FDA approved a drug label claiming that icosapent ethyl benefitted certain people at high risk for cardiovascular disease.

But questions arose soon after the study was published in 2019. True, the treatment group fared better than the placebo group. Yet a careful reading of the results suggested that this may have been because those in the placebo group had more heart attacks and strokes over time, not because the treatment group had fewer.

A follow-up study shows a different result

Responding to these questions, the study’s authors performed additional analyses. This time they looked at substances in the blood called biomarkers associated with cardiovascular risk. They found little change in the biomarker results among participants receiving the active drug. But biomarkers worsened in the placebo group, suggesting that the apparent benefit conferred by the drug may have been due to the negative effects of the placebo!

How can a placebo worsen cardiovascular risk? One possibility is that the mineral oil placebo used in this trial may have reduced absorption of statin drugs participants were taking to lower their cholesterol, which also affects heart and blood vessel health. Regardless, this new analysis suggests that the skepticism about the dramatic results of the original study was appropriate, and additional study is warranted.

The bottom line

For me, this story has three take-home points:

  • There are many ways for research to come to faulty conclusions; an unfortunate placebo choice is an unusual one but appears to be true here.
  • For medical research to be trusted, researchers must be willing to accept criticism, re-assess findings, and perform additional analyses if necessary.
  • It appears that in the case of REDUCE-IT, this self-correction process worked.

After the initial study in 2019, enthusiasm was high for the drug icosapent ethyl. In the wake of this latest analysis, however, that excitement is likely to wane. But one thing should be clear: this is not science being unable to make up its mind, as is sometimes said. Reassessment and correction, when warranted, is how science is supposed to work.

Bible verses for today’s meditation and inspiration: Matthew E. McLaren

2 Corinthians 13:9 For we rejoice when we ourselves are weak but you are strong; this we also pray for, that you be made complete.

Colossians 1:28 We proclaim Him, admonishing every man and teaching every man with all wisdom, so that we may present every man complete in Christ.

Colossians 4:12 Epaphras, who is one of your number, a bondslave of Jesus Christ, sends you his greetings, always laboring earnestly for you in his prayers, that you may stand perfect and fully assured in all the will of God.

2 Corinthians 10:15-16 not boasting beyond our measure, that is, in other men’s labors, but with the hope that as your faith grows, we will be, within our sphere, enlarged even more by you, so as to preach the gospel even to the regions beyond you, and not to boast in what has been accomplished in the sphere of another.

2 Thessalonians 1:3 We ought always to give thanks to God for you, brethren, as is only fitting, because your faith is greatly enlarged, and the love of each one of you toward one another grows ever greater;

2 Peter 3:18 but grow in the grace and knowledge of our Lord and Savior Jesus Christ To Him be the glory, both now and to the day of eternity. Amen.

Ephesians 1:17-18 that the God of our Lord Jesus Christ, the Father of glory, may give to you a spirit of wisdom and of revelation in the knowledge of Him. I pray that the eyes of your heart may be enlightened so that you will know what is the hope of His calling, what are the riches of the glory of His inheritance in the saints,

Ephesians 3:16-19 that He would grant you, according to the riches of His glory, to be strengthened with power through His Spirit in the inner man, so that Christ may dwell in your hearts through faith; and that you, being rooted and grounded in love, may be able to comprehend with all the saints what is the breadth and length and height and depth, read more

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