Cancer therapeutics–related cardiac dysfunction induced by anthracycline is highly problematic, and its early recognition is of importance. Atrial fibrillation (AF) is sometimes seen after anthracycline chemotherapy. We aimed to test whether new-onset AF predicts anthracycline-induced heart failure. We prospectively studied 249 lymphoma patients who received anthracyclines. The patients were followed up with a frequent electrocardiographic examination. Fifteen patients (6%) newly developed AF after the chemotherapy, and during a mean follow-up of 34 months, they had a higher incidence of acute heart failure (40% vs 3.8%; p <0.001) and greater all-cause mortality (60% vs 14.1%; p <0.001) than those without AF. The onset of AF preceded the development of heart failure by a mean of 2.4 months. New-onset AF was independently associated with both acute heart failure (hazard ratio 12.78; p <0.001) and all-cause mortality (hazard ratio 4.77; p <0.001). The cumulative anthracycline dose did not differ between the patients with and without heart failure, yet it was another independent predictor of the mortality. In conclusion, new-onset AF may predict unfavorable outcomes after anthracycline chemotherapy in patients with malignant lymphoma.
Anthracyclines are widely used chemotherapeutic agents; however, they are related to cancer therapeutics–related cardiac dysfunction (CTRCD), with a prevalence of 6% on average. Atrial fibrillation (AF) is the most common arrhythmia, and it is known that its occurrence is occasionally seen in patients receiving anthracyclines. We, thus, hypothesized that the development of AF prognosticates an acute decompensated anthracycline-induced heart failure. The aim of the present study was to test this hypothesis in patients with malignant lymphoma who were treated with anthracycline chemotherapy.
Methods
The present study was a prospective observational study and was conducted in the Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital. We considered consecutive patients ≥18 years eligible for inclusion if they were scheduled to receive anthracycline chemotherapy for the treatment of Hodgkin’s or non-Hodgkin’s lymphoma in the hospital from April 2009 to March 2013.
Patients were ineligible for enrollment if they had a history of congestive heart failure, structural heart disease, or known AF. The study protocol was approved by the institutional review board of the hospital. The stage of lymphoma was defined in accordance with the Ann Arbor classification. The chemotherapeutic regimens we principally used were ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) for Hodgkin’s disease and CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) or R-CHOP (CHOP with rituximab) for non-Hodgkin’s disease. The total dose of anthracyclines was expressed as a doxorubicin-equivalent dose. An echocardiogram using standardized methods and electrocardiogram were carried out before the chemotherapy in all patients. Blood samples were collected before the chemotherapy for laboratory data. The patients were scheduled to be seen in the outpatient clinic every month after the chemotherapy. The electrocardiogram was repeated at each clinical visit to detect any arrhythmias including AF. AF was defined according to the current guidelines. The patients were strictly instructed to be seen in the outpatient clinic or emergency department when they felt palpitations or a disturbed pulse.
The end points of the present study were (1) the development of AF, (2) development of acute heart failure defined in the current guidelines that required a hospitalization, and (3) all-cause mortality.
The continuous variables were summarized as the means ± SD and categorical variables as proportions. A Mann-Whitney U test was used to compare the normally distributed variables. Comparisons of the paired data were done by means of a Wilcoxon signed-rank test. A Kaplan-Meier analysis was used to assess the time required for the end points to occur. The log-rank test was applied to compare the event-free survival between the patient groups. Cox proportional hazard models were used to determine the predictors of the end points. Variables with a p value <0.1 in the univariate models were included in the multivariate models. All statistical analyses were performed with the use of JMP software, version 11.0 (SAS Institute, Cary, North Carolina). A p value <0.05 was considered significant.
Results
We finally studied 249 patients. The clinical characteristics of the patients studied are listed in Table 1 . We found 15 patients (6%) who newly developed AF after starting the chemotherapy during a mean follow-up period of 34 ± 9 months ( Figure 1 ). Among the 15 patients with AF, 3 developed paroxysmal AF and remaining 12 had persistent AF.
| Variable | |
|---|---|
| Age (years) | 67±13 |
| Male | 121 (49%) |
| Body mass index (kg/m 2 ) | 22.7±3.8 |
| Non-Hodgkin’s disease | 237 (95%) |
| Ann Arbor stage | |
| I | 32 (13%) |
| II | 40 (16%) |
| III | 37 (15%) |
| IV | 140 (56%) |
| Hypertension | 74 (30%) |
| Hyperlipidemia | 32 (13%) |
| Diabetes mellitus | 33 (13%) |
| Estimated glomerular filtration rate (ml/min/1.73m 2 ) | 73.1±22.7 |
| Brain natriuretic peptide (pg/ml) | 45.8±59.5 |
| Left atrial diameter (mm) | 33.1±6.2 |
| Left atrial volume index (ml/m 2 ) | 33.8±14.5 |
| Left ventricular ejection fraction (%) | 69±10 |
| Left ventricular end-diastolic volume index (ml/m 2 ) | 55.8±16.3 |
| Interventricular septum thickness (mm) | 9.0±1.7 |
| E/e’ lateral | 7.5±4.2 |
We found 15 patients (6%) who newly developed acute heart failure requiring hospitalization during the follow-up period. Acute CTRCD was not suspected in any of the patients. The left ventricular ejection fraction significantly decreased from baseline during the hospitalization for acute heart failure (56.1 ± 13.8% to 43.5 ± 19.0%; p <0.001). The cumulative anthracycline dose did not differ between the patients with and without heart failure (274.6 ± 123 mg/m 2 vs 277 ± 75.8 mg/m 2 ; p = 0.9). The patients with AF were more likely than those without to develop acute heart failure (40% vs 3.8%; p <0.001, Figure 2 ), and the onset of AF preceded the occurrence of heart failure in all of them. The time from the AF onset to the development of heart failure was 2.4 ± 2.8 months. A lower left ventricular ejection fraction at baseline and the development of AF were found to be independent predictors of the development of acute heart failure ( Table 2 ).
| Variable | Univariate | Multivariate | ||
|---|---|---|---|---|
| Hazard ratio (95% CI) | P-value | Hazard ratio (95% CI) | P-value | |
| Age >65 years | 1.41 (0.51-4.21) | 0.51 | ||
| Ann Arbor stage IV | 0.46 (0.14-1.32) | 0.16 | ||
| Male | 1.16 (0.42-3.30) | 0.78 | ||
| Hypertension | 1.76 (0.54-5.00) | 0.32 | ||
| Diabetes mellitus | 1.98 (0.45-6.25) | 0.33 | ||
| Estimated glomerular filtration rate <60 ml/min/1.73m 2 | 2.83 (0.94-7.92) | 0.06 | 1.6 (0.43-6.07) | 0.47 |
| Brain natriuretic peptide >50 pg/ml | 1.44 (0.69-3.04) | 0.34 | ||
| Left atrial diameter >40 mm | 6.27 (0.82-38.34) | 0.07 | 1.29 (0.28-9.4) | 0.76 |
| Left ventricular ejection fraction <50 % | 4.64 (1.01-15.78) | 0.05 | 9.07 (1.7-41.1) | 0.01 |
| E/e’ lateral >12 | 1.52 (0.87-2.92) | 0.15 | ||
| Cumulative anthracycline dose >400 mg/m 2 | 1.33 (0.07-6.67) | 0.79 | ||
| Atrial fibrillation | 28.95 (8.47-104.07) | < 0.001 | 12.78(3.36-52.96) | < 0.001 |
During the follow-up period, 16.9% of the patients died. Worsening primary disease accounted for the majority of the causes of death ( Table 3 ). The patients with AF had a higher mortality than those without (60% vs 14.1%; p <0.001, Figure 3 ). Multivariate analyses revealed that an increased cumulative anthracycline dose and the development of AF were independently associated with the all-cause mortality ( Table 4 ). Complete remission was achieved in 216 patients (86.7%).
| Variable | |
|---|---|
| Heart failure | 1 (2%) |
| Myocardial infarction | 1 (2%) |
| Worsening primary disease | 26 (62%) |
| Myelodysplastic syndrome | 1 (2%) |
| Solid cancers | 4 (10%) |
| Hepatitis | 4 (10%) |
| Bleeding | 1 (2%) |
| Sepsis | 2 (5%) |
| Unknown causes | 2 (5%) |
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