CI confidence interval LVEF left ventricular ejection
CI, confidence interval; LVEF, left ventricular ejection fraction.
Calvillo-Argüelles et al. Statins and Trastuzumab Cardiotoxicity
Table 3. Multivariable logistic regression model (cardiotoxicity as dependent variable)
CI, confidence interval; OR, odds ratio.
* Diabetes, hypertension, coronary artery disease, and smoking.
Inhibition of these pathways through trastuzumab results in alterations in mechanical coupling, aggravated by imbalance in calcium (Ca2þ) homeostasis, causing impaired contrac-tility and relaxation and subsequent cardiac dysfunction.18 Accordingly, the attenuation of these effects by statins might be the basis for the observed outcomes in our study. In support of this hypothesis, a recent study of rats treated with doxorubicin and trastuzumab demonstrated worsened LV function and greater ROS and glutathione production compared with treatment with doxorubicin alone.19 The worsening of LV function and ROS and glutathione pro-duction were blunted by rosuvastatin. Therefore, we postu-late that the Linezolid effects of HMG-CoA reductase inhibitors may account for our observed results but acknowledge that further mechanistic studies are needed.
The cardiotoxicity risk of 20.2% based on the CREC definition seen in our study is similar to the incidence that has been reported in other studies and is not surprising given the high cardiovascular risk profile of our study population.20-22 We have demonstrated recently that in patients with at least 1 cardiovascular risk factor (age 60 years, hypertension, diabetes, coronary artery disease, or atrial fibrillation), the 5-year cumulative incidence of a major adverse cardiac event (heart failure [HF] hospitalization, HF diagnosis, or cardio-vascular death) can be as high as 8.2% in patients receiving nonanthracycline, trastuzumab-based chemotherapy and 11.3% in patients exposed to anthracyclines followed by trastuzumab.2 Thus, the potential use of primary prevention strategies in such high-risk patients receiving trastuzumab therapy is clinically relevant.
Primary prevention with statins
Although other studies have shown a similar cardioprotective effect of statins in patients treated with anthracyclines,7,8 our study is the first to demonstrate this effect in trastuzumab-treated patients. Although more than half of our patients also received anthracyclines prior to tras-tuzumab therapy, the effect remained significant after adjustment for anthracycline use, and the magnitude of effect of statins was similar in those who did and did not receive anthracycline therapy.
The fact that substantial cardioprotective effect was observed in the statin group despite a presumed higher cardiovascular risk due to higher prevalence of traditional cardiovascular risk factors is an important finding. This may reflect the fact that these traditional risk factors may increase the risk of heart failure in the mid- to long-term follow-up but be less relevant 157
Figure 1. Subgroup analysis comparing the benefit of concomitant use of statins in patients who did and did not receive anthracyclines prior to trastuzumab therapy.
for LVEF changes that occur during cancer therapy, as has been demonstrated in previous studies.23,24 Also, the patients in the statin group were more likely to be treated with renin-angiotensin system inhibitors and b-blockers than the control group owing to their cardiovascular comorbidities. Even though the use of these medications can be viewed as a potential confounder, the protective effect with statins was maintained even after adjustment for exposure to these thera-pies. Moreover, modern cardio-oncology trials have not
uniformly supported the cardioprotective effects of b-blockers and ACE inhibitors in patients similar to ours.13,25 The
cardioprotective benefit of statins despite higher risk of cardiovascular disease (CVD) has also been reported in a pro-spective observational study in which 14 patients treated with statins had a smaller change in cardiac magnetic resonance image (MRI)-measured LVEF after anthracycline treatment than 37 controls, despite a higher cardiovascular risk and lower baseline LVEF.9 Here, we extend these findings to patients receiving trastuzumab therapy.
We also identified a lower incidence of CREC-defined cardiotoxicity in statin-treated patients in our adjusted anal-ysis. However, given the wide confidence interval around the odds ratio and the borderline P value, we consider this to be only hypothesis generating. Furthermore, trastuzumab inter-ruption was lower in the statin-treated patients, although the difference did not meet statistical significance. We were unable to perform adjusted analysis because of the small number of events. Larger studies are required to further assess the impact of statin therapy in preventing cardiotoxicity and interruption of trastuzumab treatment in women with HER2þ breast cancer.