Cardiovascular safety profile of combretastatin a4 phosphate in a single-dose phase I study in patients with advanced cancer.

PURPOSE: The purpose of our study was to review and determine the cardiovascular safety profile of combretastatin A4 phosphate (CA4P) in a Phase I study in 25 patients with advanced solid tumors. EXPERIMENTAL DESIGN: CA4P was administered in a dose-escalating fashion starting at 18 mg/m(2) i.v. every 21 days, and the maximal dosage was 90 mg/m(2). Continuous evaluation included bedside blood pressure and pulse monitoring, 12-lead electrocardiogram (ECG) at fixed time points for measured QT interval determination, determination of the corrected QT interval (QTc) using Bazett's formula QTc = QT/(R-R interval)(1/2), and chart review. Pharmacodynamic correlations of CA4P dose, CA4P/CA4 area under the curve, and C(max) versus heart rate (HR), blood pressure, QT, and QTc intervals, over the first 4 h postdosing were analyzed. RESULTS: After CA4P administration, there were significant increases in QTc interval at the 3-h and 4-h time points [27.2 ms (P < 0.0001) and 30.8 ms (P < 0.0001), respectively] and HR at the 3- and 4-h time points [13.2 beats per minute (bpm; P < 0.01) and 15.1 bpm (P < 0.001), respectively]. Three of 25 patients had prolonged QTc intervals at baseline, whereas 15 (60%) of 25 and 18 (75%) of 24 patients had prolonged QTc intervals at 3 and 4 h. The slope of HR and QTc increasing as a function of time during the first 4 h was correlated to dose (in milligrams) of CA4P (P = 0.01 and r = 0.49 for HR, P = 0.005 and r = 0.55 for QTc) and to CA4 area under the curve (P = 0.04 and r = 0.41 for HR, P = 0.02 and r = 0.44 for QTc); blood pressure and uncorrected QTc interval dose-response correlations were not significant. Two patients had ECG changes consistent with an acute coronary syndrome within 24 h of CA4P infusion. CONCLUSIONS: CA4P prolongs the QTc interval. There was a temporal relationship with the CA4P infusion and with ECG changes consistent with an acute coronary syndrome in two patients. It is advisable that future trials with CA4P have eligibility guidelines limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more experience is gained regarding potential cardiovascular toxicity with this agent.

Heart failure in women.

The incidence of congestive heart failure in the US population is increasing as more women and men survive with chronic hypertensive and atherosclerotic heart disease. Almost half the patients in the US with heart failure are women. Hypertension, diabetes mellitus, and cigarette smoking are all more potent risk factors for the development of heart failure in women than in men. Important differences in presentation and mortality explain gender differences in the clinical course of heart failure. Overall mortality is lower for women than for men with symptomatic heart failure. Some but not all of this difference can be explained by a lower rate of ischemic heart disease. Standard treatments for congestive heart failure, including angiotensin converting enzyme inhibitors and beta-blockers, have been shown to be equally efficacious in men and in women. Preliminary data on angiotensin II receptor blockers suggests equivalent benefit with further trial data awaited. Peripartum cardiomyopathy is a form of heart failure unique to women, occurring in the last stages of pregnancy or within 5 months after delivery. Approximately half of affected women regain normal ventricular function but for those who do not, the risk of recurrent symptomatic heart failure and mortality during subsequent pregnancies is high.