Chipping Away at Chemotherapy-Induced Cardiotoxicity

Patrice Wendling

March 15, 2018

ORLANDO — Two studies failed to meet their primary endpoints but still suggest cardioprotective benefits with two common heart drugs in patients receiving two key breast cancer drugs.

In the Carvedilol for Prevention of Chemotherapy-Induced Cardiotoxicity (CECCY) trial, use of the β-blocker carvedilol (Coreg, GlaxoSmithKline) did not affect left ventricular ejection fraction (LVEF) at 6 months in patients receiving anthracyclines but had beneficial effects on a key cardiac biomarker and diastolic function.

In the second trial, carvedilol and the angiotensin-converting enzyme inhibitor lisinopril (Prinivil, Merck; Zestril, AstraZeneca) also failed to significantly prevent cardiotoxicity in patients treated with trastuzumab (Herceptin, Genentech), but both drugs reduced cardiotoxicity in the high-risk group of patients treated with both trastuzumab and anthracyclines.

The results were presented in a late-breaking clinical trial session here at the American College of Cardiology (ACC) 2018 Annual Scientific Session.

"These two trials are really important trials…I really do think we're going to start to see some practice change," session chair, Christopher M O'Connor, MD, Inova Heart and Vascular Institute, Falls Church, Virginia, said in an interview.

"The resistance has been mostly been on the oncologists," he added. "They give multiple drugs for treating cancer, but they're nervous about low doses of really safe cardiovascular drugs. So I think there's a lot of education to do, but this going to be the future."

CECCY Trial of Carvedilol

The CECCY trial enrolled 200 patients with breast cancer and normal LVEF and randomly assigned them to placebo or carvedilol (maximal tolerated dose, 18.5 mg/day) at the start of anthracycline chemotherapy (cumulative dose, 240 mg/m2). Patients underwent echocardiography and blood tests at baseline, after each chemotherapy cycle, and at the end of chemotherapy at around 24 weeks. 

Mean ages were 51 years in the carvedilol group and 53 years in the placebo group; neoadjuvant therapy was used in 58.3% and 43.7% and adjuvant therapy in 41.6% and 54.1%, respectively. Palliative therapy was used only in two controls.

At 6 months, the primary endpoint of at least a 10% decrease in LVEF occurred in 15% of patients treated with carvedilol and 14% given placebo (P = .84), according to the results, simultaneously published in the Journal of the American College of Cardiology.

B-type natriuretic peptide levels, which increase during heart failure, were also similar in the two groups.

Compared with placebo, however, carvedilol significantly reduced levels of the cardiac biomarker troponin I (P = .003) and the percentage of patients with diastolic dysfunction (30.2% vs 39.3%; P = .039) and was associated with a trend toward less decreased LV end-diastolic diameter (P = .057).

"Our results suggest carvedilol might reduce myocardial injury, might influence the LV remodeling process in the cardiotoxicity setting, and might decrease the appearance of diastolic dysfunction," reported trial author Mônica Samuel Avila, MD, Clinical Hospital of Medical School of São Paulo, Brazil.

The discordance between the increase in troponin without a change in LVEF is difficult to explain, but Avila said the elevation in troponins was mild, which may reflect myocardial injury but may not be expressive enough to affect myocardial function. Differences also could appear with longer follow-up, which is planned for up to 2 years.

"I wonder if this trial was done on the cardiac MRI platform if they might have seen differences there because with MRI you can detect differences in LVEF by 2% but not with echo. It doesn't have that accuracy," panelist and chair of ACC's new cardio-oncology section, Ana Barac, MD, Medstar Health, Washington, DC, said in an interview.

She drew parallels between CECCY and the recent PRADA trial, which showed that patients with early breast cancer taking the angiotensin receptor blocker candesartan (Atacand, AstraZeneca) had significantly lower declines in LVEF on cardiac MRI.

"Most importantly, we have the tools now to go to the oncology community and say, 'Why don't we start studying women with hypertension who have to be on other drugs?'" Barac said. "Many of these women are healthy and are not going to have problems from the cardiovascular side, but there are women with an ejection fraction of 51% starting anthracyclines and they need our help."

Barac said acceptance of adding cardiovascular drugs to cancer treatment protocols varies from one hospital to the next and that she was particularly moved by Avila's comments, which earned a round of applause from the audience: Avila  described how she went patient by patient to get 200 of nearly 1100 women screened into the trial.

"As a collaborative effort we have moved," but "it's a culture change," Barac said.

During a media briefing, ACC cardio-oncology council member Bonnie Ky, MD, director of the University of Pennsylvania Cardio-Oncology Center of Excellence in Philadelphia, said, "Many people are asking, 'How do I start a cardio-oncology center?' and her study is a perfect example of how persistence, dedication, and caring can really make this possible and feasible."

Ky said she believes carvedilol can attenuate myocardial injury but that it's critically important to look at the longer-term changes in ejection fraction (EF).

"We know that changes in EF usually occur about 1 to 2 years after the initiation of chemotherapy, and I expect to see that we will see a benefit with carvedilol there," Ky said. "I also think it could be important to look at core lab-adjudicated ejection fraction because we know that that can reduce the variability in this measure."

Trastuzumab Trial

The second trial enrolled 468 patients with HER2-positive breast cancer and normal LVEF starting trastuzumab therapy and randomly assigned them to receive once-daily lisinopril 10 mg, carvedilol 10 mg, or placebo. Half were receiving or had received anthracycline-based chemotherapy. Cardiotoxicity was defined as a decrease in baseline LVEF of at least 10% at follow-up or an absolute decrease of at least 5% in LVEF if it was less than 50% at follow-up.

Most patients were white (86.3%), their mean age was 51 years, and their mean baseline LVEF was 63%.

After 2 years' follow-up, the probability of cardiotoxicity was similar for lisinopril, carvedilol, and placebo in the whole cohort.

However, among the cohort receiving trastuzumab and anthracyclines, the probability of cardiotoxicity was significantly lower with carvedilol (hazard ratio [HR], 0.49; 95% CI, 0.27 - 0.89; P = .009) and lisinopril (HR, 0.53; 95% CI, 0.30 - 0.94; P = .015) than with placebo, study author Maya Guglin, MD, PhD, University of Kentucky, Lexington, said.

Adverse cardiac effects were similar across the three groups, occurring in 29% of patients receiving carvedilol, 30% receiving lisinopril, and 32% receiving placebo. Low blood pressure and dizziness were the most common adverse events and were milder in the carvedilol group.

"In patients who may benefit from an anthracycline-containing regimen, the prophylactic use of lisinopril or carvedilol is justified and should be considered," Guglin said.

"I do believe interpreting this trial in the context of all the other data to date that these two medications do have a cardioprotective benefit," Ky said. "What does this mean for me in my practice? I think high-risk patients should likely be prophylactically treated with these medications."

Ky told | Medscape Cardiology that the 2017 American Society of Clinical Oncology (ASCO) guidelines on cardiac dysfunction identified high-risk patients and that "they would be patients receiving sequential anthracyclines with trastuzumab, patients receiving high-dose anthracyclines, receiving modest-dose anthracyclines plus radiation therapy, and those with an increased burden of cardiovascular risk factors, such as hypertension, dyslipidemia, or obesity."

As to whether these data can be extrapolated to patients with other types of cancer, Ky said, "If I were seeing a patient in clinic with increased cardiovascular risk factors or receiving high-dose anthracyclines, I would very strongly consider it but have that one-on-one patient discussion: 'There is this compelling data, are you willing?'"

Ky noted that some oncologists are pulling away from anthracyclines and trastuzumab because of the concern for cardiotoxicity. "But perhaps we can envision a paradigm where we perform risk-benefit analysis, [to determine] what's the benefit in terms of oncologic outcome, we mitigate that cardiotoxic risk with these medications, and then overall in the long term we hopefully have improved oncologic outcomes."

Guglin observed that about 30% to 35% of oncologists she's spoken with said they prefer to treat with anthracyclines and would treat more patients if they felt safer about cardiovascular side effects.

The CECCY trial was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo as part of Avila's doctoral thesis. The authors report having no financial relationships to disclose. The trastuzumab trial was cosponsored by the University of South Florida and the National Cancer Institute. O'Connor reports receiving consultant fees/honoraria from Actelion, Bayer, Bristol-Myers Squibb, Merck, and Resmed; ownership interest, partnership, or serving as a principal for Biscardia; and research grants from Roche. Barac reports having no relevant financial disclosures. Ky reports receiving a research grant from Roche.

American College of Cardiology (ACC) 2018 Annual Scientific Session. Presentations 405-12 and 405-14. Both presented March 11, 2018.

J Am Coll Cardiol. Published online March 11, 2018. Abstract

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