Anthracyclines are an important component of cancer treatments; however, their use is limited by the occurrence of cardiotoxicity. There are limited data on the occurrence of heart failure and the value of baseline and follow-up measurements of left ventricular (LV) ejection fraction (EF) in the current era. Therefore, the objectives of the present study were twofold: (1) to characterize the occurrence of and risk factors for major adverse cardiac events (MACEs: symptomatic heart failure and cardiac death) in a large contemporaneous population of adult patients treated with anthracyclines and (2) to test the value of LVEF and LV dimensions obtained using echocardiography in the prediction of MACE. Five thousand fifty-seven patients were studied, of whom 124 (2.4%) developed MACE. Of the total cohort, 2,285 patients had an available echocardiogram pre-chemotherapy. Patients with MACE were older (p <0.0001), predominantly men (p = 0.03), and with a higher incidence of cardiovascular risk factors and cardiac treatments. Patients with hematologic cancers had a higher incidence of cardiac events than patients with breast cancer (4.2% vs 0.7%, p <0.0001). Baseline LVEF, LVEF ≤5 points above the lower limits of normal, and LV internal diameter were predictive of the rate of occurrence of MACE. In conclusion, older patients with hematologic cancers and patients with a baseline LVEF ≤5 points above the lower limit of normal have higher incidence of MACE and should be closely monitored.
The cardiotoxicity of anthracyclines is well recognized, with a risk of symptomatic heart failure (HF) between 2% and 5% reported in studies performed in the 1970 and 1990s. Early studies demonstrated the usefulness of monitoring left ventricular ejection fraction (LVEF) derived by nuclear methods during treatment to predict symptomatic HF. However, the dose of anthracyclines that is used currently is significantly lower, and echocardiography has replaced nuclear imaging as the most common technique to measure LVEF. Moreover, 2 recent retrospective studies have questioned the utility of measuring a baseline LVEF in all patients. Finally, whether other echocardiographically derived measures, such as LV size, are useful in the prediction of symptomatic HF in patients treated with anthracyclines is unknown. The objectives of the present study were twofold: (1) to detail the occurrence of and risk factors for symptomatic HF and cardiac death (major cardiac events) in a large contemporaneous population of patients treated with anthracyclines and (2) to evaluate the role of echocardiographically derived LVEF and LV dimensions measured before chemotherapy in the prediction of symptomatic HF and cardiac death in patients treated with anthracyclines.
Methods
All consecutive patients (≥18 years) who were diagnosed with cancer and underwent anthracycline-based chemotherapy at Massachusetts General Hospital (MGH) from January 1, 2002, to October 1, 2012, were selected. We then identified all patients who had a transthoracic echocardiogram at MGH performed before the start of chemotherapy. The starting date of the anthracycline therapy was considered the study entry date. The study protocol was approved by the institutional review board.
Clinical characteristics included gender, age, type of cancer, adjunctive therapy, cardiac risk factors including hypertension, diabetes, hyperlipidemia, smoking status, previous cardiomyopathy or coronary artery disease, and concomitant medications. The primary outcome was the subsequent occurrence of major adverse cardiac event (MACE) defined as either the New York Heart Association class III or IV congestive HF, cardiac arrest, or cardiac death. Outcomes were obtained through review of the institutional electronic medical records and were verified by a board-certified cardiologist blinded to all other clinical data. Loss of follow-up because of noncardiac-related mortality was also verified.
All echocardiograms were 2-dimensional transthoracic echocardiograms and were interpreted by cardiologists at MGH. The parameters available from the echocardiograms included the anteroposterior dimension of the LV cavity at end-diastole (left ventricular internal diameter [LVID]), the anteroposterior dimension of the LV cavity at end-systole, and the LVEF. The LVEF was calculated from a parasternal long-axis view anteroposterior dimension measurement.
Descriptive statistics including mean ± SD, median and interquartile (twenty-fifth to seventy-fifth) range, and frequencies for continuous and categorical data are presented. To determine if having a baseline echocardiogram at MGH was associated with high cardiac risk, we investigated whether patients without echocardiograms at MGH had had an evaluation of cardiac function either by another method or outside MGH. First, the nuclear medicine database at MGH was queried. The charts of a random sample of 100 patients (10 per year) among the patients who did not have an echocardiogram or a nuclear-gated blood-pool scan at MGH were then analyzed to determine whether they had had a cardiac function assessment outside MGH. The characteristics of patients with an available echocardiogram who developed or did not develop clinical events were compared using the Student’s t tests for normally distributed continuous variables, Wilcoxon rank-sum tests for non-normally distributed continuous variables, and chi-square or Fisher’s exact tests for categorical variables. Patients who had not experienced a cardiac event as of their last visit date were censored at this date. Kaplan-Meier survival curves were used to estimate cardiac event-free survival. When a significant difference was found, pairwise comparison of the survival was done. Proportional hazard analysis was used to analyze the univariable effect of the demographic, clinical, and echocardiographic (continuous) characteristics on the occurrence of cardiac events. To investigate the possibility that confounding by clinical variables accounted for the association of cancer type, LVEF, and LVID with MACE, we tested whether cancer type, LVEF, and LVID were independent predictors of MACE after controlling for the major clinical risk factors. All statistical analyses were performed using the JMP statistical package (SAS Institute Inc., Cary, North Carolina).
Results
Five thousand fifty-seven patients were treated with anthracyclines at MGH from 2002 to 2012. Of these, 2,285 patients (45%) had an echocardiogram with an available report (performed at MGH) before the initiation of anthracyclines. The clinical characteristics of the 2,285 patients with an available echocardiogram report are summarized in Table 1 . Of the remaining patients, 834 patients (16%) underwent a multiple-gated blood-pool scan (MUGA) at MGH. Based on the analysis of 100 randomly selected charts of the 1,938 patients with no echocardiogram or MUGA at the MGH, 81% of these patients had an echocardiogram or a MUGA at an outside facility before anthracycline treatment. Thus, only 368 patients (7.3% of the initial 5,057 patients) had no documented evaluation of cardiac function before treatment. There was no difference in the follow-up period of patients who had an available echocardiogram and the other patients treated with anthracyclines (p = 0.25).
| Variables | Entire Cohort (n=2285) | Cardiac Event (n=65) | No Cardiac Event (n=2220) | P (CE vs. no CE) | |
|---|---|---|---|---|---|
| Age (years) | 53 ± 16 | 61 ± 14 | 53 ± 16 | <0.0001 | |
| Male | 936 (41%) | 36 (53%) | 936 (42%) | 0.03 | |
| Followup (days) | 675[193-1666] | 588[155-1872] | 675[194-1666] | 0.78 | |
| Type and dose of anthracycline (mg/m 2 ) | Daunorubicin (147) | 98 [30-204] | 61[27-208](17) | 98 [30-204](130) | 0.81 |
| Doxorubicin (2034) | 223[88-267] | 224[87-267](1998) | 206[140-262] (1463) | 0.84 | |
| Epirubicin (46) | 198[100-295] | 308(1) | 196[100-295](45) | N/A | |
| Idarubicin (64) | 12[8-19] | 12[7-17](12) | 12[8-20] (52) | 0.33 | |
| Cancer Type | Breast | 711 (31%) | 5 (8%) | 706 (32%) | <0.0001 |
| Blood | 1122 (49%) | 47 (72%) | 1075 (48%) | ||
| Others | 452(20%) | 13 (20%) | 439 (20%) | ||
| CV history | CAD | 137 (6%) | 13 (19%) | 124 (6%) | 0.02 |
| Cardiomyopathy | 96 (4%) | 12 (18%) | 84 (4%) | 0.03 | |
| Hypertension | 344 (15%) | 16 (25%) | 328 (15%) | 0.047 | |
| Diabetes Mellitus | 202 (9%) | 15 (23%) | 187 (8%) | 0.001 | |
| Hyperlipidemia | 155 (7%) | 6 (9%) | 149 (7%) | 0.5 | |
| Smoker | 65 (3%) | 4 (6%) | 61 (3%) | 0.13 | |
| CV treatment | Beta-Blocker | 342(15%) | 19 (29%) | 323 (15%) | 0.002 |
| ACEI or ARB | 104(5%) | 6 (9%) | 94 (4%) | 0.069 | |
| Statin | 185(8%) | 8 (12%) | 177 (8%) | 0.26 | |
| LVID (mm) | 45±5 | 46±6 | 44±5 | <0.0001 | |
| LVIS (mm) | 28±4 | 30±5 | 28±4 | <0.0001 | |
| Baseline LVEF | 68 ±7 | 64±10 | 68±7 | <0.0001 |
Sixty-five patients from the 2,285 (2.8%) developed severe symptomatic HF or cardiac death (MACE). There was no difference in the occurrence of MACE in the 2,285 patients who had an available transthoracic echocardiogram and the 2,772 patients who did not (2.8% vs 2.1%, p = 0.10, occurrence for the whole cohort 2.4%). The MACE occurred at a median of 198 days (63 to 650 days) after the initiation of anthracyclines; this delay was greater in patients with breast cancer than in patients with hematologic cancers or other malignancies (620 days [207 to 2,170 days] vs 166 days [48 to 334 days] and 134 days [50 to 456 days], respectively, p = 0.0032).
The baseline echocardiogram was performed at a median of 7 days before the initiation of anthracyclines (range 3 to 20 days). The mean LVEF was 68 ± 7%. A total of 45 patients (2%) had an abnormal baseline LVEF according to the updated guidelines, 112 (5%) were within 5% units above the lower limits of normal (54 ≤ LVEF ≤59% for women and 52 ≤ LVEF ≤57% for men), and 2,128 were ≥6% units above the lower limits of normal. The mean LVID was 45 ± 5 mm. Based on the guidelines, 18 patients (1%) had an enlarged baseline LVID.
Patients who developed cardiac events were older (p <0.0001), predominantly men (p = 0.03), and with a higher incidence of risk factors and pre-existing cardiac history and treatment by β blockers, ACEI, or ARB. Interestingly, the anthracycline dose was similar in the 2 groups. Patients with hematologic cancers had a higher incidence of MACE than those with breast cancer (4.2% vs 0.7%, p <0.0001) for a similar duration of follow-up (p = 0.34). Of note, the overall mortality was also higher in patients with hematologic cancers than in patients with breast cancer (27% vs 13%, p <0.0001). Patients with hematologic cancer had more cardiovascular risks factors than patients with breast cancer (60% men vs 0%, higher rate of a pre-existing history of hypertension [17% vs 14%, p = 0.0012] and diabetes [10% vs 6%, p = 0.005]) and received slightly higher doses of doxorubicin (239 [129 to 290 mg/m 2 ] vs 207 [188 to 230 mg/m 2 ], p = 0.01). The univariate analysis of the baseline, clinical, and echocardiographic predictors of MACE is presented in Table 2 . When adjusted for age, gender, previous cardiomyopathy and CAD, hypertension, and diabetes, cancer type remained an independent predictor of MACE (p = 0.0009).
