Bernard J. Gersh

Cardiac Safety Analysis of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With or Without Trastuzumab in the North Central Cancer Treatment Group N9831 Adjuvant Breast Cancer Trial

PURPOSEnTo assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial.nnnPATIENTS AND METHODSnPatients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18 to 21 months.nnnRESULTSnOf 2,992 patients completing AC, 5.0% had LVEF decreases disallowing trastuzumab (decrease below normal: 2.4%, decrease > 15%: 2.6%). There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy. Cardiac events (congestive heart failure [CHF] or cardiac death [CD]): arm A, n = 3 (2 CHF, 1 CD); arm B, n = 19 (18 CHF, 1 CD); arm C, n = 19 (all CHF); 3-year cumulative incidence: 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event in arms B and C: older age (P < .003), prior/current antihypertensive agents (P = .005), and lower registration LVEF (P = .033). Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8% to 10%; LVEF recovered and trastuzumab was restarted in approximately 50%.nnnCONCLUSIONnThe cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF, and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC.

Beneficial six-year outcome of smoking cessation in older men and women with coronary artery disease. Results from the CASS registry.

We investigated the effects of cigarette smoking and cessation of smoking in a cohort of 1893 men and women from the Coronary Artery Surgery Study (CASS) registry who were 55 years of age or older and had angiographically documented coronary artery disease. The six-year mortality rate was greater among continuing smokers (n = 1086) than among those who quit smoking during the year before enrollment in the study and abstained throughout the study (n = 807) (relative risk, 1.7 [95 percent confidence limits, 1.4, 2.0]). Continuing smokers were also at higher risk of either myocardial infarction or death (1.5 [1.2, 1.7]). There was no diminution of the beneficial effect with increasing age. The relative risks of death were 1.7 (1.4, 2.1) and 1.6 (1.1, 2.3) for the groups 55 to 64 years old and 65 or older, respectively, and 1.6 (1.4, 1.9) for comparable subgroups among CASS subjects 35 to 54 years of age. When subjects were arrayed according to risk quartile, the benefits of smoking cessation were greatest in those at moderate risk. We conclude that smoking cessation lessens the risk of death or myocardial infarction in older as well as younger persons with coronary artery disease.

The utility of clinical, electrocardiographic, and roentgenographic variables in the prediction of left ventricular function

To determine the clinical value of simple, widely available variables in estimating left ventricular (LV) function, we performed an analysis on 14,507 patients presenting with chest pain who were enrolled in the Coronary Artery Surgery Study registry. Of these patients, 4,034 had a normal electrocardiogram, and of these, 91.8% had an LV ejection fraction (EF) > 0.50, 7.6% had an EF of 0.36 to 0.50, and only 0.6% had an EF < or = 0.35. The presence of T-wave abnormalities (with normal QRS), left bundle branch block, electrocardiographic evidence of LV hypertrophy or myocardial infarction, cardiomegaly on chest roentgenogram, basilar rales, or third heart sound significantly decreased the likelihood of normal LVEF. Based on these clinical variables, a logistic regression model with a sensitivity of 68% and a specificity of 74% for identifying subjects with normal EF was developed. It was concluded that in patients with chest pain, consideration of such readily available clinical data provides useful information and may decrease the need for more expensive imaging methods.