Cardioprotective drugs may be unnecessary during early breast cancer treatment

The cardioprotective drugs metoprolol and candesartan had little benefit on cardiovascular (CV) outcomes when given alongside adjuvant anthracycline treatment in women with early breast cancer and low CV risk, long-term results of the PRADA* trial showed.

“Candesartan and metoprolol during adjuvant therapy for early breast cancer did not protect against long-term decline in left ventricular ejection fraction (LVEF),” said lead author, cardiovascular radiologist Dr Siri Lagethon Heck from Akershus University Hospital, Lørenskog, Norway.

“If patients don’t have pre-existing heart conditions or high CV risks from the start … it seems to be relatively safe to administer adjuvant therapy. In this patient group, the therapy isn’t as dangerous as previously thought, and in general, patients should not be afraid that their cancer therapy will harm their heart,” she said at the 2021 Scientific Sessions of the American College of Cardiology (ACC.21).

Participants in this single-centre, double-blind study were 120 women aged 18–70 years with early-stage breast cancer, normal kidney function, and LVEF ≥50 percent. They were randomized 1:1:1:1 to receive candesartan cilexetil (target dose: 32 mg/day), metoprolol succinate (target dose: 100 mg/day), both, or placebos, alongside their adjuvant anthracycline-containing breast cancer therapies. Women with significant CV disease, prior chemotherapy or radiotherapy exposure, and prior treatment with or intolerance to ACE** inhibitors, ARBs**, or beta-blockers were excluded.

Trial drugs were administered throughout adjuvant treatment (10–61 weeks). Patients underwent cardiovascular magnetic resonance at baseline and at a median 23 months follow-up.

At follow-up, reduction in LVEF from baseline did not differ between groups (-1.7 percent [candesartan], -1.8 percent [no candesartan], -1.6 percent [metoprolol], -1.9 percent [no metoprolol]), with no significant differences between the candesartan and no candesartan (p=0.91) and metoprolol and no metoprolol (p=0.73) groups. [ACC.21, abstract 21-LB-21218-ACC; Circulation 2021;doi:10.1161/CIRCULATIONAHA.121.054698]

The results did not significantly differ according to anthracycline dose level.

The treatments did not affect troponin concentrations. Changes in hs cardiac troponin I and hs cardiac troponin T were 1.2 and 0.6 ng/L, respectively, in the candesartan group, 1.9 and 1.6 ng/L in the no candesartan group, 1.4 and 1.0 ng/L in the metoprolol group, and 1.7 and 1.2 ng/L in the no metoprolol group.

LV end-diastolic volume and peak global longitudinal strain (GLS) decline did not differ between the metoprolol and no metoprolol groups at follow-up (difference, -1 mL; p=0.78 [LV end-diastolic volume] and difference, -0.4 percent; p=0.34 [GLS]). However, there was a greater reduction in LV end-diastolic volume with candesartan vs no candesartan during adjuvant therapy (difference, -6 mL; p=0.021), while peak GLS decline was attenuated (difference, -0.8 percent; p=0.046).

Heart failure incidence did not significantly differ between groups. LV mass did not significantly differ between the candesartan vs no candesartan groups (p=0.75) or between the metoprolol and no metoprolol groups (p=0.66), nor did end-systolic volume (p=0.086 and p=0.75, respectively) or NT-proBNP levels (p=0.087 and p=0.22, respectively).

Who needs cardioprotective drugs?

“Overall, there is limited evidence that general, primary preventive neurohormonal blockade provides significant long-term clinical benefit. Future trials should focus on whether … neurohormonal blockade [is] more efficient in patients at higher risk of developing cardiac dysfunction,” the authors said.

They noted that the present study population may have had a lower risk of cardiotoxic effects of anthracycline given that they were “relatively young, without serious comorbidities, and treated with low to moderate anthracycline doses.”

“Our findings indicate that contemporary adjuvant therapy for early breast cancer is safe in these patients,” they said.

“Cardioprotective treatment with these drugs may give the patients side effects and should not be given routinely when it’s not needed,” pointed out Heck. “[Instead,] we want to try to identify the patients who are at higher risk for heart problems and who might benefit more from cardioprotective drugs.”

The authors highlighted the smaller-than-expected LVEF reduction in the study population, which suggests a potential lack of power to detect between-group differences. Longer follow-up may also have yielded different results.