Can Chemotherapy Cardiotoxicity Be Prevented?
Abstract & Commentary
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
Source: Cardinale D, et al. Prevention of High-Dose Chemotherapy-Induced Cardiotoxicity in High-Risk Patients by Angiotensin-Converting Enzyme Inhibition. Circulation. 2006;114:2474-2481.Granger, CB. Predictiion and Prevention of Chemotherapy-Induced Cardiomyopathy. Circulation. 2006;114:2432-2433.
The cardiotoxicity of anthracyclines and other agents may negatively affect clinical outcomes in cancer survivors. Data in other clinical situations and animal data on anthracycline-induced cardiomyopathy suggests that angiotensin-converting enzyme inhibitors (ACEI) may ameliorate this cardiotoxicity. Thus, Cardinale and co-workers performed a prospective randomized trial of 473 patients undergoing high-dose chemotherapy (HDC), of whom 114 showed a troponin I (TnI) release of > 0.07 ng/ml within 72 hours of the end of the first cycle of HDC. They were randomized to receive enalapril titrated to a maximum dose of 20 mg/day or nothing, which was started one month after the last cycle of HDC and continued for one year. The primary endpoint was an absolute decrease in left ventricular (LV) ejection fraction (EF) of 10% and a value below 50%. There were no significant differences in baseline characteristics between the 2 groups and the cumulative anthracycline doses were 332 ± 191 (SD) in the ACEI group and 338 ± 167 in the controls (p = NS). Average early TnI levels were 0.18 ± 0.38 and 0.22 ± 0.44, respectively (P = NS). All patients tolerated enalapril at a mean dose of 16 ± 6 mg/day. Baseline EF was 62 ± 3 and 63 ± 3, respectively. Results: 25 controls (43%) vs no ACEI patients showed a decrease in EF meeting the primary endpoint (p < .001). ACEI patients had smaller LV volumes and a higher EF at 12 months (62% vs 48%, P < .001). Cardiac events occurred in one ACEI patient (arrhythmia) and 30 controls (14 heart failures) p < 0.001. Also, in the control group a persistently elevated TnI was associated with a lower EF. The authors concluded that in high-risk HDS patients, early and continued treatment with ACEI prevents late cardiotoxicity and associated adverse clinical events.
Commentary
This is a good example of a concept that worked in animal models, translating nicely to humans. ACEI have been shown to have anti-remodeling effects in post-myocardial infarction patients and to preserve LV function in early class I LV dysfunction patients, so it is not a big stretch to the cardiotoxicity drug arena. However, the mechanism of this protective effect is unknown. This raises the issue of whether the toxic effects of HDC were abrogated by ACEI or masked by the known beneficial effects of ACEI in cardiomyopathy patients. Thus, duration of therapy becomes a concern. If damage to the myocardium is prevented, then supposedly therapy could be stopped at some point. If cardiac dysfunction is merely being masked, then therapy should be continued indefinitely. The authors argue that since ACEI worked best in those with persistent TnI release at one month, and that almost all patients have normal TnI at 12 months, that ACEI must prevent damage early and could be stopped after one year. Of note some patients in the persistent TnI release group had EFs < 50% at one year despite ACEI, so they would still have an indication for ACEI therapy. At this point it may be reasonable to stop ACEI at 12 months if TnI and LVEF are normal, but not otherwise.
This study also demonstrates how previous studies by this group lead to this successful treatment trial. In their earlier observational studies, they noted that TnI release predicted subsequent cardiotoxicity, especially if it was persistent. However, a normal TnI had a negative predictive value of 99%, so ACEI therapy could safely be withheld in these patients and they were not included in this treatment study. Also, the control group did demonstrate an increased incidence of adverse cardiac events, as would be expected, whereas the ACEI group was almost free of adverse events (one case of arrhythmias). Even if adverse events do not occur, a reduced EF limits choices for future chemotherapy if the patient relapses. Thus, these data are a powerful inducement to use ACEI in HDC patients who experience TnI release. Therapy was very well tolerated and there seems to be little downside.
There are some limitations and caveats of this study. It was not blinded and there was no placebo given, so some investigator bias cannot be excluded. Also, HDC therapy varied from patient to patient, but the total anthracycline dose was similar in both groups. In addition, only once-a-day enalapril was given at a modest dose. Higher doses and twice-a-day therapy, as has been done in heart failure trials of enalapril, could be more effective. Finally, this study represents only one approach to cardioprotection in HDS. Other therapies and approaches have also shown promise, such as beta-blockers, and specially designed chemotherapeutic regimes. This is an area that is moving fast, so stay tuned.
The cardiotoxicity of anthracyclines and other agents may negatively affect clinical outcomes in cancer survivors. Data in other clinical situations and animal data on anthracycline-induced cardiomyopathy suggests that angiotensin-converting enzyme inhibitors (ACEI) may ameliorate this cardiotoxicity.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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