Prevention of High-Dose Chemotherapy–Induced Cardiotoxicity in High-Risk Patients by Angiotensin-Converting Enzyme Inhibition

Abstract

Background-An increase in troponin I soon after high-dose chemotherapy (HDC) is a strong predictor of poor cardiological outcome in cancer patients. This finding has important clinical implications and provides a rationale for the development of prophylactic strategies for preventing cardiotoxicity. Angiotensin-converting enzyme inhibitors slow the progression of left ventricular dysfunction in different clinical settings, but their role in the prevention of cardiotoxicity has never been investigated. Methods and Results-Of the 473 cancer patients evaluated, 114 (72 women; mean age, 45Ϯ12 years) who showed a troponin I increase soon after HDC were randomized to receive (angiotensin-converting enzyme inhibitor group; 20 mg/d; nϭ56) or not to receive (control subjects; nϭ58) enalapril. Treatment was started 1 month after HDC and continued for 1 year. Cardiological evaluation was performed at baseline and at 1, 3, 6, and 12 months after HDC. The primary end point was an absolute decrease Ͼ10 percent units in left ventricular ejection fraction, with a decline below the normal limit value. A significant reduction in left ventricular ejection fraction and an increase in end-diastolic and end-systolic volumes were observed only in untreated patients. According to the Kaplan-Meier analysis, the incidence of the primary end point was significantly higher in control subjects than in the angiotensin-converting enzyme inhibitor group (43% versus 0%; PϽ0.001). Conclusions-In high-risk, HDC-treated patients, defined by an increased troponin I value, early treatment with enalapril seems to prevent the development of late cardiotoxicity.

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

“…Observational studies and small randomized clinical trials suggest a benefit in early initiation of angiotensin‐converting enzyme inhibitors and beta‐blockers for the prevention of cardiotoxicity 15, 89, 90, 91, 92, 93. The PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial tested whether angiotensin receptor blockers and/or beta‐blockers would be effective in preventing cardiotoxicity in patients diagnosed with breast cancer receiving anthracycline‐based chemotherapy with and without trastuzumab.…”

Cardiac Imaging: Multimodality Advances and Surveillance Strategies in Detection of Cardiotoxicity

“…Cardinale et al demonstrated that the timing and degree of Tn-I rise was predictive of developing LV dysfunction, and also correlated with anthracycline cumulative dosing [43][44][45][46]. Tn-I monitoring also served effectively as risk stratification in their studied population; patients treated with high-dose chemotherapy who developed an increased in Tn-I were the ones who benefited more from the initiation of an angiotensin-converting enzyme inhibitor treatment (enalapril), preventing LVEF decrease [47]. In addition, an increase in Tn-I was associated with a 17.6 times increased risk of cardiotoxicity, and emerged as the only independent predictor of lack of recovery in LVEF despite treatment with HF therapy, which consisted of enalapril and carvedilol upbeing titrated to maximally tolerated doses used in conventional HF [48].…”

“…Troponin elevations during treatment also identify a high risk cohort of cancer patients who may benefit from early cardioprotective medication [47]. Natriuretic peptides are strong predictors of elevated LV pressure and HF.…”

The Cardioprotective Role of Naca in the Prevention of Doxorubicin and Trastuzumab Mediated Cardiac Dysfunction

“…Increased ANG II causes a decrease in NRG-1 protein levels, ultimately reducing the amount of a key regulator in cell survival signaling pathways. 68 In addition, ANG II also inhibits the already reduced amount of NRG-1 from binding to the HER-4 receptor, thus severely reducing the activation of cell survival pathways. 68 Finally, ANG II also binds to the angiotensin 1 receptor, which activates a cascade resulting in the production of reactive oxygen species (ROS).…”