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Carvedilol for primary prevention of chemotherapy-related cardiotoxicity in the CECCY Trial: Ready for prime time?

Great discussion exists among cardiologists about the best strategy to prevent and/or treat cancer therapy related cardiac dysfunction (CTRCD): left ventricular ejection (LV) fraction (EF), assessed by echocardiography, and biomarkers (mainly troponin I) are actually used in the clinical practice to start cardio-protective therapy. Cardiac Imaging Associations have recently proposed algorithms based on the determination of global longitudinal strain, obtainable by advanced speckle tracking echocardiography, as a marker of early LV dysfunction [1,2]. This issue has an absolute clinical relevance as the diagnosis of overt CTRCD often induces clinicians to hold or stop otherwise effective cancer therapies or to apply a suboptimal cancer treatment regimen. Accordingly, as underlined in a recent Expert Consensus of European Society of Cardiology [2], the development of evidence-based cardioprotective strategies is a main unmet need in cardio-oncology.



The CECCY Trial [3] - published on JACC May 2018 - suggests an alternative way by applying cardioprotective therapy a priori in cancer patients, i.e., at the beginning of cancer therapy and independent of the evidence of cardiac symptoms/signs. This trial evaluated the role of carvedilol as a primary prevention intervention in 192 HER2-negative breast cancer patients undergoing contemporary dose anthracycline (ANT) chemotherapy. Patients were randomized to receive placebo or carvedilol (up-titrated every 3 weeks till the maximal dosage of 50 mg daily). The primary end-point was prevention of ≥ 10% reduction in EF at 6 months. Secondary outcomes were effects of carvedilol on troponin I, B-type natriuretic peptide and diastolic dysfunction. The primary endpoint-prevention of reduction in EF of ≥10 percentage points from baseline to 6 months was not reached (about 14% in both the carvedilol and placebo group), but the carvedilol group achieved secondary endpoints (lower increase in troponin levels and LV end-diastolic diameter and lower incidence of grade I diastolic dysfunction). The authors conclude that in patients undergoing ANT chemotherapy, carvedilol could prevent or delay the onset of cardiac damage and adverse cardiac remodeling.

The background of the CECCY Trial is represented by pre-clinical literature supporting antioxidant and anti-apoptotic effects of beta-blockade on the myocardial injury determined by ANT. Notably, a previous large retrospective study in patients treated by ANT with or without anti-HER2 monoclonal antibody trastuzumab, suggested that beta-blocker therapy was associated with a lower incidence of overt heart failure [4].      In this context, the CECCY Trial represents the largest randomized trial of beta-blockade for the primary prevention of ANT cardiotoxicity.       

While the findings of the CECCY Trial can generate some degree of enthusiasm on prophylactic beta-blockade in this clinical setting, they should also be judged with caution. The Editorial of accompaniment on JACC [5] rises some doubts about the application of the suggested strategy in the clinical practice. It highlights how the low incidence of abnormal LV systolic function after contemporary chemotherapy counters a primary prevention strategy under these circumstances (ANT therapy alone) and considers unclear whether troponin-based management effectively improves cardiovascular outcomes in this specific patient population. Authors of a letter regarding the CECCY Trial [6] note that only 37.4% of recruited patients were up-titrated to a surely effective carvedilol daily dose (28.1% at 25 mg and 9.3% at 50 mg) and that detailed information on heart rate values, the number of patients reaching a desirable heart rate target or on the possible influence of blood pressure on carvedilol titration, are lacking in the article. Could the failure in the primary endpoint be at least partially explained by the non-achievement of a sufficiently low heart rate or blood pressure? Indeed, in the rebuttal letter the authors of the CECCY Trial provide more detailed information on blood pressure and heart rate during the follow-up the patients treated by carvedilol. Nevetherless. these issues remain crucial in a clinical setting that often experiences ANT side effects such as vomit, diarrhea, and anemia, which induce hypovolemia and hypotension and possibly hinder the use of acceptable carvedilol dosages. According to these perspectives, the potentially important protective effect of carvedilol should be carefully balanced with tolerability and tailored in individual patients.      

The CECCY Trial therefore highlights the need for additional, randomized controlled trials of preventive beta-blockade in larger populations as well as in patients with higher risk of severe LV dysfunction and heart failure, such as those needing high-dose ANT chemotherapy or ANT followed by trastuzumab. In parallel, additional efforts should be devoted on defining the late consequences of an asymptomatic depression of LV systolic function and optimizing risk prediction in the delicate setting of oncologic patients. The optimal strategy to prevent overt cardiotoxicity in cancer patients remains still unclear and to be defined.                                  


           

 

 

 

 

 

 

 

 

References

  1. Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2014;15:1063-1093-
  2. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016;37:2768-2801.
  3. Avila MS, Ayun-Ferreira SM, de Barros Wanderley MR Jr., et al. Carvedilol for prevention of chemotherapy-related cardiotoxicity: the CECCY trial. J Am Coll Cardiol 2018;71:2281-90.
  4. Seicean S, Seicean A, Alan N, et al. The cardioprotective effect of beta-adrenoreceptor blockade in patients with breast cancer undergoing chemotherapy: follow-up study of heart failure. Circ Heart Fail 2013;6:420-426.
  5. Asnani A. Beta-Blockers for Primary Prevention of Anthracycline Cardiotoxicity. Not quite ready for prime time. J Am Coll Cardiol 2018;71:2291-92.
  6. Galderisi M, Sorrentino R, Esposito R. Can carvedilol prevent chemotherapy-related cardiotoxicity? A dream to be balanced with tolerability: J Am Coll Cardiol 2018;72:1181-1182.