COMMENTARY

Preventing Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) Investigators Interviewed

John M. Mandrola, MD

Disclosures

November 24, 2015

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Editor's Note: At the 2015 American Heart Association (AHA) Scientific Sessions in Orlando, Florida, John M. Mandrola, MD, interviewed the investigators for the Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) trial, Geeta Gulati, MD, and Torbjørn Omland, MD, PhD, from the University of Oslo and the Akershus University Hospital, Lorenskog, in Norway.

Dr Mandrola: Hi, everyone. This is John Mandrola from theheart.org on Medscape. I'm here at the AHA sessions in Orlando, and I'm pleased to have with me a cardiology fellow, Geeta Gulati, and Professor Omland from Oslo, Norway.

They're here to discuss their late-breaking clinical trial called PRADA[1]—the Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy. Welcome.

Dr Gulati: Thank you.

Dr Omland: Thank you.

Dr Mandrola: Geeta, tell us about the trial.

PRADA Overview

Dr Gulati: Breast cancer is the most common cancer among women worldwide, and overall survival has increased from about 60% in the 1960s to up to 90%. Survival has improved significantly. So now it's time to look at the side effects of treatment because that's actually becoming a problem. One of the side effects that's really concerning to the cardiologist is the cardiotoxic effect of anticancer treatment.

Dr Mandrola: Right. So what did you do?

Dr Gulati: We wanted to see if the cardiotoxicity could be prevented in the breast cancer population, so we gave them normal heart failure medication, which is very common—candesartan and metoprolol, during the cancer treatment. And then we looked at heart function using cardiac MRI, before they started anticancer treatment and then after, so we could see if the medication, the preventive medication, had an effect.

Dr Mandrola: And this was an actual randomized controlled trial. Tell us about that.

Dr Gulati: This was a randomized, placebo-controlled, double-blind trial in a homogeneous population, the breast cancer population. And we used a 2 x 2 factorial design so that we could compare two medications and see the effect without losing too much power.

Dr Mandrola: And you found some surprising results?

Dr Gulati: Our major finding was that candesartan actually had a preventive effect in these patients, or at least it prevented a decline in left ventricular ejection fraction.

Dr Mandrola: And metoprolol?

Dr Gulati: We found no significant effect with metoprolol.

Anticancer Treatment and Cardiotoxicity

Dr Mandrola: You were alluding to the background of why you decided to do this trial: Things have changed quite a bit in breast cancer, or in cancer therapy.

Dr Gulati: For anticancer treatment now, for breast cancer especially, anthracycline is a cornerstone; it's very important. And it has a dose-dependent cardiotoxicity, so you cannot give very high doses of anthracycline because that would give you more cardiotoxicity. One in every six women will receive trastuzumab in addition to the anthracycline, and both of these medications together have a very bad effect on the heart.

Dr Mandrola: And that's where prevention of the cardiotoxicity comes in.

Dr Gulati: Yes, that's right.

Previous Trials

Dr Mandrola: What have previous trials about cardiotoxicity prevention shown? Or have there been previous trials?

Dr Gulati: There have been previous trials, but most of them are in a heterogeneous population, and very few have studied prevention. It is well known that there is cardiotoxicity from anthracyclines and trastuzumab.[2] Also, the previous studies in these heterogeneous populations usually used echocardiography, which is less accurate and has maybe more variability than cardiac MRI.

Dr Mandrola: Do you believe that MRI is more sensitive or more reliable?

Dr Gulati: Well, cardiac MRI is the gold standard for ejection fraction, but in an everyday clinic, it's not easy for all of us to access. That's why usually echocardiography or multigated acquisition (MUGA) scan is done to look at the ejection fraction.

Dr Mandrola: But your study used MRI.

Dr Gulati: Actually, we used both MRI and echocardiography.

Dr Mandrola: Explain this 2 x 2 factorial design—exactly how does that work?

Dr Omland: The 2 x 2 factorial design means that we're testing two drugs in the same trial without losing any statistical power. We randomly assigned patients to candesartan and placebo and to metoprolol and placebo. That means that 25% of patients will receive two placebos, and 25% of patients will receive both drugs. Then 25% will receive either only candesartan, or, the last group, only metoprolol.

Dr Mandrola: And when you looked at the primary endpoint, what exactly were you looking at, just a change in ejection fraction?

Dr Gulati: We were looking at the contiguous change in that left ventricular ejection fraction in these patients, and that's where we found the significant result—that there was a larger decline in the placebo group vs the candesartan group.

Dr Mandrola: And the decline in the placebo group was about the same as the decline in the metoprolol group, is that right?

Dr Omland: That's correct.

Dr Mandrola: But, for some reason, candesartan seems protective.

Dr Gulati: That's correct.

Dr Mandrola: What do you think the clinical implications of that finding are?

Dr Gulati: This is a very interesting finding; follow-up studies are necessary, of course, to see what this will mean in the future for these patients. But there are observational studies showing that an early decline is associated with risk for cardiac dysfunction later on.

Why Not Beta-Blockers?

Dr Mandrola: Can you speculate why beta-blockers weren't protective? I'm sort of a beta-blocker guy, being an electrophysiologist. I was surprised to see that. Is there some mechanistic reason why?

Dr Omland: One explanation is that beta-blockers do not really interfere with the direct cardiotoxic effect of the drug. It may have an effect in the long term or with the development of more severe dysfunction over time, but in the early phase, it's probably other mechanisms.

Dr Mandrola: That leads me to the next question I wanted to ask you. This was a pretty short-term study, correct?

Dr Gulati: Yes, this was a study where we looked at the decline just after the anticancer treatment.

Dr Mandrola: And what about long term—do you have plans to carry this on long term?

Dr Gulati: Yes, the long-term follow-ups are already in progress.

Dr Mandrola: Do you expect any change in long-term follow-up vs short-term, based on, maybe, the chemotherapeutic drugs used?

Dr Gulati: If you look at previous studies that have been done, we do expect to see [change]; but, of course, it's difficult to say—again, because the previous studies were in a heterogeneous group, and they used higher doses of anthracycline than what is used in the breast cancer population.

Dr Mandrola: We were talking before about one of the things that we might be able to do—if we can prevent cardiotoxicity, we might be able to improve the efficacy of cancer chemotherapeutics.

Dr Gulati: I think that's also a really important point regarding prevention because we've seen how anticancer treatment is more and more focused on individual patients, and clinicians don't want to treat everyone with the same regimen. That means that maybe they want to find patients who really need the anticancer treatment, especially with anthracyclines, and maybe give them higher doses. But then the cardiotoxicity for anthracycline is dose-dependent...

The Future of Cardio-Oncology Trials

Dr Mandrola: Professor, what do you see, looking into the future, about the future of cardio-oncology trials? Do you think that we'll be using ejection fraction as a surrogate, or we'll be using other outcomes? Is it important?

Dr Omland: Ejection fraction is an important index of cardiac function, but I still think that we all agree that it would be desirable, with larger scale trials, if we actually could look at the clinical endpoints.

Dr Mandrola: And, of course, a hot topic these days is individualizing therapy, precision medicine.

Dr Omland: Correct.

Dr Mandrola: Do you see that here as well in cardio-oncology?

Dr Omland: I think that's a very important point, also, in cardio-oncology. And I think the PRADA study database, which also includes biomarker measurements, etc., will enable us to look into whether we can identify predictors of development of cardiac dysfunction over time. That's not what we are going to present here at the AHA meeting, but that is certainly something we will look very deeply into in the future.

Changing Practice?

Dr Mandrola: I wanted to ask you: These findings—how have they changed your practice, or have they changed your practice?

Dr Gulati: The field of cardio-oncology is getting more and more attention. So because of this study, and, of course, because of other studies as well, in our hospital there is now better collaboration between the cardiologist and oncologist.

What we want to do, or what we have started to do, in our hospital is that the cardiologists have actually started their own outpatient clinic especially for the oncologic patients, so that we can do an evaluation of the heart before they start chemotherapy. And then it will be easier to follow up with them and see if they need more or other cardioprotective medication.

Dr Mandrola: Is this just for breast cancer or any oncology problem?

Dr Gulati: Mostly it is for the patients receiving anthracycline or trastuzumab, so mainly breast cancer patients, but also patients with hematologic cancers.

Dr Mandrola: And did I understand you correctly that all patients in the oncology clinic who are expected to get these drugs will see a cardiologist?

Dr Gulati: That's the idea.

Dr Mandrola: That's great. Thank you very much for being here, both of you. I appreciate it.

Dr Omland: Thank you.

Dr Mandrola: That's it from the AHA sessions. This is John Mandrola from theheart.org on Medscape.

Disclosures: Torbjørn Omland, MD, has disclosed the following relevant financial relationships: Received research grants from: AstraZeneca Pharmaceuticals LP, Abbott Diagnostics; received income in an amount equal to or greater than $250 from: Abbott Diagnostics, Roche Diagnostics; serve(d) as a consultant for Novartis Pharmaceuticals Corporation. Geeta Gulati, MD, has disclosed the following relevant financial relationships: AstraZeneca Pharmaceuticals LP provided study medication free of charge.

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