Which chemotherapy agent is most likely to cause congestive heart failure: 5-fluorouracil (5-FU), platinum, doxorubicin, methotrexate, or tamoxifen?

Doxorubicin (Anthracycline) is the Most Likely Agent to Cause Congestive Heart Failure

Among the chemotherapy agents listed, doxorubicin carries by far the highest risk of congestive heart failure, with incidence ranging from 4% to >36% at cumulative doses of 500-550 mg/m², making it the most cardiotoxic agent in this group. 1

Comparative Cardiotoxicity Profile

Doxorubicin (Anthracycline) - HIGHEST RISK

• Anthracyclines are the most cardiotoxic chemotherapeutic drugs, with doxorubicin specifically causing dose-dependent cardiomyopathy and heart failure. 1
• The cardiotoxicity manifests in three patterns: acute (<1% incidence with transient contractility decrease), early-onset chronic (1.6%-2.1% within first year), and late-onset chronic (occurring up to 10-30 years after treatment). 1
• The mechanism involves free radical formation and apoptosis of myocardial cells, leading to irreversible myocardial damage. 1
• Risk escalates dramatically with cumulative dose, with the 500-550 mg/m² threshold representing a critical inflection point. 1, 2

5-Fluorouracil - ISCHEMIA, NOT HEART FAILURE

• 5-FU primarily causes coronary vasospasm and myocardial ischemia, not congestive heart failure. 3, 4, 1
• The most common manifestation is angina-like chest pain (1-68% incidence), with ischemic ECG changes in 68% of symptomatic patients. 3, 1
• Cardiac events typically occur within 2-5 days of administration and are usually short-lasting (up to 48 hours). 4
• The pathophysiology involves coronary artery thrombosis, vasospasm, and direct endothelial injury—not the chronic cardiomyopathy seen with anthracyclines. 3, 1

Platinum Agents (Cisplatin) - THROMBOSIS, NOT HEART FAILURE

• Cisplatin increases risk of thrombotic events such as deep vein thrombosis or pulmonary embolism. 3
• Specific cardiotoxicity causing heart failure is rarely reported with platinum agents. 3

Methotrexate - MINIMAL CARDIAC RISK

• Methotrexate is not listed among the primary cardiotoxic chemotherapy agents in major guidelines. 3, 1
• It does not have a recognized association with congestive heart failure.

Tamoxifen - THROMBOTIC RISK, NOT HEART FAILURE

• Tamoxifen is primarily associated with thromboembolic complications, not direct cardiotoxicity or heart failure.
• It is not classified among chemotherapeutic agents with significant cardiomyopathy risk. 3, 1

Clinical Implications for Monitoring

Pre-Treatment Assessment for Anthracyclines

• Baseline echocardiogram with LVEF measurement is mandatory for all patients receiving anthracyclines, especially those with cardiovascular risk factors, age >60 years, previous CVD, or prior mediastinal irradiation. 3, 2
• LVEF <54% represents a contraindication or requires alternative regimens. 2

Risk Factors That Amplify Anthracycline Cardiotoxicity

• High cumulative dose remains the dominant risk factor. 1, 5
• Rapid infusion time (<30 minutes), female sex, extremes of age (very young or advanced), and underlying cardiovascular disease all increase risk. 1
• Concurrent use of cyclophosphamide, trastuzumab, or paclitaxel dramatically amplifies cardiotoxicity—trastuzumab combined with anthracyclines increases heart failure incidence to 27%. 3, 1

Monitoring During Treatment

• Serial LVEF measurements at baseline, 3,6, and 9 months during treatment, and 12 and 18 months after initiation are essential. 2
• Cardiac biomarkers (troponin I and BNP) should be measured periodically to identify at-risk patients. 2

Critical Pitfalls to Avoid

• Do not confuse 5-FU's ischemic cardiotoxicity with the chronic cardiomyopathy caused by anthracyclines—they have completely different mechanisms, time courses, and management strategies. 3, 4, 1
• Do not underestimate late-onset anthracycline cardiotoxicity—heart failure can manifest decades after treatment completion, requiring lifelong surveillance. 1
• Do not exceed cumulative anthracycline dose limits without compelling oncologic justification and enhanced cardiac monitoring. 2, 5