Letter by Hammoud et al Regarding Article “Prevention of High-Dose Chemotherapy–Induced Cardiotoxicity in High-Risk Patients by Angiotensin-Converting Enzyme Inhibition”
To the Editor:
With great interest we read the article by Cardinale et al,1 who randomized 114 cancer patients with elevated troponin I to either enalapril 20 mg/d or no treatment 1 month after high-dose chemotherapy. The investigators found that patients treated with angiotensin-converting enzyme inhibitors (ACEI) had an impressive reduction in cardiotoxicity (defined as a decline in left ventricular ejection fraction >10% below 50%) compared with those who did not receive treatment. In addition, they noted a significantly lower incidence of adverse cardiac events in the group of patients treated with enalapril.
The results from this study further support the antiinflammatory and antioxidant effect of inhibition of the renin-angiotensin system. This certainly suggests a potential role for ACEI as a method of primary prevention of chemotherapy-induced cardiotoxicity.2 However, it is not reported by these investigators whether the control group was started on medical therapy if they were found to have a decline in their ejection fraction during the course of the investigation. A significant number of these subjects went on to develop left ventricular dysfunction, and medications such as ACEIs would be the current standard of care.3
In a previous study, 25 patients with doxorubicin-induced cardiomyopathy (mean 6.4±4.9 years after their chemotherapy) were randomized to ACEI, angiotensin receptor blockers or combination of ACEI and β-blockers. These patients showed a significant increase in ejection fraction only in the combination group, and patients in the ACEI group showed a trend toward normalization of left ventricular ejection fraction but not improvement.4 Thus, it seems plausible that ACEI must be started early after administration of high-dose chemotherapy to prevent cardiac complications. If ACEI were given in the control group and these patients still had a decline in their ejection fraction, it brings into question how long these patients should be treated. Is treatment only beneficial during the period of acute oxidative injury? If patients were not started on ACEI, then the application of these results to a larger population where patients would be started on ACEI and β-blockers also comes into question. Thus, in our opinion, it is crucial to clarify whether ACEIs were used in the control group in this study before these results are applied to the target population.
Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, Martinelli G, Veglia F, Fiorentini C, Cipolla CM. Prevention of high-dose chemotherapy–induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006; 114: 2474–2481.
Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2005; 46: e1–e82.