Bevacizumab-treated patients had a 1.6% incidence of high-grade CHF compared with 0.4% incidence in patients who received placebo. The difference translated into a relative risk of 4.74, investigators reported in the Journal of Clinical Oncology.
The risk was similar with low- and high-dose bevacizumab regimens.
"Although the overall incidence [of CHF] remains low, the relative risk is significant," Toni K. Choueiri, MD, of Dana-Farber Cancer Institute in Boston, and co-authors wrote in conclusion.
"Physicians and investigators should be aware of this adverse effect and should monitor patients receiving bevacizumab closely to offer early intervention and to optimize the balance between oncologic clinical benefit and life-threatening adverse events."
The finding drives another stake into bevacizumab's bid to become a standard therapy for advanced breast cancer. In December the FDA began taking steps to revoke the drug's accelerated-approval status for breast cancer, following a review that failed to show a survival benefit in those patients.
An inhibitor of vascular endothelial growth factor (VEGF), bevacizumab and other members of the class carry a known risk of adverse cardiovascular effects, including hypertension, proteinuria, impaired wound healing, bleeding, and arterial and venous thromboembolism, Choueiri and co-authors wrote in their introduction.
Additionally, evidence from preclinical models suggested that inhibition of the VEGF pathway could disrupt cardiac remodeling and lead to heart failure.
Clinical trials of bevacizumab in advanced solid tumors have yielded sporadic reports of CHF in patients treated with the drug. However, the issue had not undergone systematic and comprehensive scrutiny, providing a rationale for the meta-analysis, the authors noted.
A literature review, including abstracts presented at selected meetings, initially produced 60 studies of bevacizumab, which Choueiri and colleagues subsequently whittled down to five randomized, controlled trials involving a total of 3,784 patients with advanced breast cancer.
The trials included only patients with adequate organ, coagulation, and hematologic function, and protocols typically excluded patients with hypertension, clinically significant CHF, cerebrovascular or peripheral vascular disease, unstable angina, or recent MI.
During follow-up, 36 of 2,366 patients treated with bevacizumab developed clinically significant CHF compared with four of 1,418 patients in control or placebo-treated groups. The small absolute difference proved to be statistically significant (P=0.001).
Subgroup analysis show no significant difference in CHF incidence in patients treated with 2.5 versus 5.0 mg/kg of bevacizumab or according to the different cytotoxic chemotherapy regimens that patients received.
The authors pointed out that the clinical trials included in the analysis did not include data on low-grade (asymptomatic) CHF or left ventricular dysfunction.
"Asymptomatic cardiac dysfunction portends a poor prognosis, with progression to asymptomatic heart failure at a rate of 9.7% per year, and has a three-year mortality rate of 16% in the absence of medical treatment," the authors wrote.
"This type of risk may be of greatest relevance in earlier-stage breast cancer settings, as the safety of adjuvant bevacizumab exposure in breast cancer survivors is unknown."
The findings and conclusions should be interpreted with "extreme caution," authors of an accompanying editorial wrote.
"Performing a meta-analysis with retrospectively collected heart failure data adds little to our current body of evidence," according to Nitin Verma, MD, and Sandra M. Swain, MD, of Washington (D.C.) Hospital Center.
"On the basis of the limitations of the study, we still lack convincing evidence that bevacizumab is associated with an increased risk of significant heart failure. It is extremely important to address this question more rigorously in randomized prospective trials to determine the magnitude of the potential risk, time of onset, and reversibility of heart failure with bevacizumab."
Bevacizumab's association with CHF is not a new observation, according to the drug's manufacturer.
"The rate of CHF reported by Choueiri et al is consistent with the incidence and severity described in the Avastin U.S. prescribing information," Genentech officials said in a statement. "The Avastin U.S. prescribing information states that in patients with metastatic breast cancer, the incidence of serious (Grade 3-4) CHF was increased in patients who received Avastin plus paclitaxel chemotherapy, compared to those who received paclitaxel alone (2.2% vs. 0.3%).
"The rate of CHF among patients who received prior anthracyclines for metastatic breast cancer was 3.8% for patients who received Avastin plus paclitaxel compared with 0.6% for patients who received paclitaxel alone."
Choueiri disclosed relationships with Bayer/Onyx Pharmaceuticals, Novartis, GlaxoSmithKline, Genentech, Eisai, and Aveo. Several co-authors also disclosed various types of relationships with commercial interests.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Journal of Clinical OncologySource Reference: Choueiri TK, et al "Congestive heart failure risk in patients with breast cancer treated with bevacizumab" J Clin Oncol 2011; DOI: 10.1200/JCO.2010.32.9060.