Should Clinical Trial Results Expire? REDUCE-AMI Study

If you work as a clinical pharmacist or spend any time working in cardiology, you've likely heard about the results from the REDUCE-AMI study. The results were published in the New England Journal of Medicine 2 weeks ago, and the findings of this study were rather damning. In essence, the study found NO BENEFIT from adding long-term beta-blocker treatment in patients with acute myocardial infarction (MI) who have a preserved ejection fraction.

For the non-clinical folks in the audience, just know that this is an extremely important finding. Some cardiologists like Dr. John Mandrola are calling it "one of the most important trials of the modern era." The reason this trial is so groundbreaking is that it tests the absence of a current standard of care. In this case, beta-blocker use post-MI has been a staple of therapy for years, and this study argues that they shouldn't be used at all.

This article will not be a journal club on REDUCE-AMI, though we will likely release one in the future. Today we're going to discuss whether or not clinical trial results should have an "expiration date". Let's talk about it.

Let's start by talking about the "burden of proof" required to get medications on the market. When the system is working appropriately, companies must prove that their drug is efficacious with a manageable safety profile. They generally meet this burden of proof by running large phase 3 clinical trials and submitting the results to a regulatory body. That regulatory body should look at the submitted data objectively, without bias, and without political motivation.

If the study is positive, then the regulatory body will allow the drug to be sold on the market. Clinicians and payers in the market can assess for themselves if the drug works based on the results of the regulatory studies. Similarly, guideline-producing organizations like the AHA and ACC can assess the study and decide whether to include it as part of their guideline recommendations. Great. Now let's imagine that the results of the study were so impactful that the drug becomes a new standard of care. Generally speaking, that's good news for all parties.

But what happens if we fast forward 20 years and the medical landscape has drastically changed over time? For instance, in cardiology, we now routinely use reperfusion therapies in patients with MI to restore blood flow to ischemic tissue. Does this mean that the basic principles established with the original landmark study should be revisited? The results of REDUCE-AMI make the answer pretty clear: yes.

Medicine changes all the time. We no longer practice bloodletting to cure disease or use cocaine to treat depression. To be fair, these are likely unfair comparisons. It's probably the case that beta-blockers actually used to work! However, with the drastic changes seen in medical practice over the years, they no longer appear to work in the current landscape. Comparatively, I don't think that bloodletting ever had real efficacy... (no comment on cocaine).

Providers should always be assessing whether or not clinical trial data is relevant to them, and they should ask themselves these questions:

• Was the comparator arm a standard of care that I would use in my practice?
• Does the patient population look anything like the patients I treat?
• Do the inclusion and exclusion criteria make sense based on what I know about the disease?

If the answer to any of these questions is "no", then the burden of proof has likely not been met for your practice (in my opinion).

Some will say that REDUCE-AMI is just one negative study and that it shouldn't be practice-changing. I tend to disagree wholeheartedly with that stance. The burden of proof we discussed earlier should be taken very seriously. A negative study is just that, negative. I don't care how wide the confidence intervals are. The burden of proof for beta-blockers post-MI has no longer been met. Their efficacy has NOT been proven in the current medical landscape, and REDUCE-AMI is evidence that they almost certainly do not work any more.

As for whether or not clinical trials should have an "expiration date", I think it depends. For myself, it comes down to the bullet points above. If old clinical trial data is based on standards of care and medical practices that are no longer relevant, I think they should be tested again. The burden of proof must be met, otherwise, how can we ethically recommend medications to patients?

*Information presented on RxTeach does not represent the opinion of any specific company, organization, or team other than the authors themselves. No patient-provider relationship is created.