Kelli N. Burger

Natural History of Paclitaxel-Associated Acute Pain Syndrome: Prospective Cohort Study NCCTG N08C1

PURPOSE The characteristics and natural history of the paclitaxel-acute pain syndrome (P-APS) and paclitaxels more chronic neuropathy have not been well delineated. METHODS Patients receiving weekly paclitaxel (70 to 90 mg/m(2)) completed daily questionnaires and weekly European Organisation for Research and Treatment of Cancer (EORTC) Chemotherapy-Induced Peripheral Neuropathy (CIPN) -20 instruments during the entire course of therapy. RESULTS P-APS symptoms peaked 3 days after chemotherapy. Twenty percent of patients had pain scores of 5 to 10 of 10 with the first dose of paclitaxel. Sensory neuropathy symptoms were more prominent than were motor or autonomic neuropathy symptoms. Of the sensory neuropathy symptoms, numbness and tingling were more prominent than was shooting or burning pain. Patients with higher P-APS pain scores with the first dose of paclitaxel appeared to have more chronic neuropathy. CONCLUSION These data support that the P-APS is related to nerve pathology as opposed to being arthralgias and/or myalgias. Numbness and tingling are more prominent chronic neuropathic symptoms than is shooting or burning pain.

Prognostic significance of impairment of heart rate response to exercise: Impact of left ventricular function and myocardial ischemia

Abstract Objectives The goal of this research was to study the association between heart rate (HR) response to exercise and the risk of death and myocardial infarction (MI) after adjustment for left ventricular (LV) function and myocardial ischemia. Background Chronotropic incompetence during exercise testing is associated with increased mortality. It is unknown whether LV dysfunction or ischemia accounts for this. Methods We studied 3,221 patients (age 59 ± 12 years; 1,701 men) who underwent treadmill exercise echocardiography. We considered two markers of chronotropic incompetence: 1) failure to achieve 85% of the maximal predicted HR, and 2) low ( Results Target HR was not achieved in 495 (15%) patients. Low chronotropic index was observed in 793 (25%) patients. There were 129 deaths (41 cardiac) during a median follow-up of 3.2 years. Myocardial infarction occurred in 65 patients. Low chronotropic index was associated with cardiac death (AR, 1.54; 95% confidence interval [CI], 1.18 to 2.04; p = 0.002) and MI (AR, 1.37; 95% CI, 1.09 to 1.69; p = 0.007). Failure to achieve 85% of maximal predicted HR was associated with increased mortality (AR, 1.49; 95% CI, 1.02 to 2.22; p = 0.04) and cardiac death (AR, 2.13; 95% CI, 1.10 to 4.17; p = 0.03). Conclusions Impaired chronotropic response to exercise is associated with increased mortality and cardiac events even after adjusting for LV function and the severity of exercise-induced myocardial ischemia.

Outcome after abnormal exercise echocardiography for patients with good exercise capacity ☆: Prognostic importance of the extent and severity of exercise-related left ventricular dysfunction

OBJECTIVES We sought to define the prognostic implications of the extent and severity of exercise echocardiographic abnormalities in patients with good exercise capacity. BACKGROUND; The exercise capacity of patients with known or suspected coronary artery disease (CAD) is of prognostic importance, as is the extent of exercise-related left ventricular (LV) hypoperfusion or dysfunction. METHODS We examined the outcomes of 1,874 patients with known or suspected CAD (mean age 64 +/- 10 years, 64% men) who had good exercise capacity (> or = 5 metabolic equivalents [METs] for women, > or = 7 METs for men) but abnormal exercise echocardiograms and analyzed the potential association between clinical, exercise and echocardiographic variables and subsequent cardiac events. RESULTS Multivariate predictors of time to cardiac death or nonfatal myocardial infarction (MI) were diabetes mellitus (risk ratio [RR] 1.88; 95% confidence interval [CI] 1.2 to 3.0), history of MI (RR 2.44; 95% CI 1.6 to 3.6) and an increase or no change in LV end-systolic size in response to exercise (RR 1.61; 95% CI 1.1 to 2.5). Using echocardiographic variables that were of incremental prognostic value, we were able to stratify the cardiac risk of the study population; cardiac death or nonfatal MI rate per person-year of follow-up was 1.6% for patients who had a decrease in LV end-systolic size in response to exercise (n = 1,330) and 1.2% for patients who did not have any severely abnormal LV segments immediately after exercise (n = 868). CONCLUSIONS In patients with good exercise capacity, echocardiographic descriptors of the extent and severity of exercise-related LV dysfunction were of independent and incremental prognostic value. Stratification of patients into low- and higher risk subgroups was possible using these exercise echocardiographic characteristics.

Phase III, Randomized, Double-Blind, Placebo-Controlled Evaluation of Pregabalin for Alleviating Hot Flashes, N07C1

PURPOSE Hot flashes are a common problem for which effective and safe treatments are needed. The current trial was conducted on the basis of preliminary promising data that pregabalin decreased hot flashes. PATIENTS AND METHODS A double-blind, placebo-controlled, randomized trial design was used to compare pregabalin at target doses of 75 mg twice daily and 150 mg twice daily with a placebo. Hot flash frequencies and scores (frequency times mean severity) were recorded daily during a baseline week and for six treatment weeks. The primary end point for this study was the change-from-baseline hot flash score during treatment week 6 between the 150 mg twice daily target pregabalin treatment and placebo. Nonparametric Wilcoxon rank sum tests, two-sample t tests, and chi(2) tests were used to compare the primary and secondary hot flash efficacy end points between pregabalin treatments and placebo. RESULTS Hot flash score changes available for 163 patients during the sixth treatment week compared with a baseline week decreased by 50%, 65%, and 71% in the placebo, and target 75 mg twice daily and 150 mg twice daily pregabalin arms, respectively (P = .009 and P = .007, comparing respective pregabalin arms to the placebo arm). While some toxicities were significantly more common in the pregabalin arms, being more evident with the higher dose, pregabalin was generally well tolerated by most patients. CONCLUSION Pregabalin decreases hot flashes and is reasonably well tolerated. A target dose of 75 mg twice daily is recommended. Its effects appear to be roughly comparable to what has been reported with gabapentin and with some newer antidepressants.

Phase III Trial of Gabapentin Alone or in Conjunction With an Antidepressant in the Management of Hot Flashes in Women Who Have Inadequate Control With an Antidepressant Alone: NCCTG N03C5

PURPOSE Despite the utility of newer antidepressants for alleviating hot flashes, antidepressants do not work adequately enough in many patients. Gabapentin is a nonhormonal agent that also can reduce hot flashes. No data have been available to address whether the combination of both agents would more effectively alleviate hot flashes, compared with gabapentin alone, in patients with inadequate hot flash control with an antidepressant alone. PATIENTS AND METHODS This was a randomized trial in which 118 patients with inadequate hot flash control on an antidepressant were randomly assigned to receive both an antidepressant and gabapentin versus being weaned off the antidepressant and receiving gabapentin alone. Patients were observed for 5 weeks (including a baseline week in which patients continued on their current antidepressant without gabapentin) during which time they completed validated daily hot flash diaries. RESULTS Ninety-one patients provided complete data at the 5-week assessment. Regardless of whether or not the antidepressant was continued when gabapentin was started, there was an approximately 50% median reduction in hot flash frequencies (54%; 95% CI, 34% to 70% for combined treatment v 49%; 95% CI, 26% to 58% for gabapentin alone) and scores (56%; 95% CI, 26% to 71% for combined treatment v 60%; 95% CI, 33% to 73% for gabapentin alone). CONCLUSION Gabapentin seems to decrease hot flashes by approximately 50% in women with inadequate hot flash control who were using an antidepressant. This study saw no significant additional hot flash reduction from continuation of the antidepressant.

Prognostic significance of the location of wall motion abnormalities during exercise echocardiography

OBJECTIVES Our aim was to determine whether location of wall motion abnormalities (WMAs) during exercise echocardiography provides independent prognostic value. BACKGROUND The effect of the location of WMAs during stress echocardiography on prognostic outcome is unknown. METHODS We studied 4,347 patients (mean age, 61 +/- 12 years; 2,230 men) with known or suspected coronary artery disease by symptom-limited exercise echocardiography. An abnormal result was defined as resting or exercise-induced WMA. End points were cardiac death and nonfatal myocardial infarction (MI). RESULTS There were 133 cardiac events (54 cardiac deaths and 79 nonfatal MIs) during follow-up (median, three years). In a multiple-stepwise multivariate analysis model, clinical and exercise electrocardiography predictors of cardiac events were age, gender, hypertension, typical chest pain, previous MI, smoking, and resting ejection fraction. The percentage of ischemic segments at peak exercise provided additional information to the model (p = 0.0001). The presence of abnormalities in the left anterior descending (LAD) coronary artery distribution had an additional independent effect for the prediction of cardiac events (p = 0.001). Among patients with exercise echocardiographic abnormalities in a single vascular region, those with abnormalities in the left anterior descending coronary artery distribution had a higher event rate than patients with abnormalities elsewhere (3.2% vs. 2.1% at three years and 10.8% vs. 2.1% at five years; p = 0.009). CONCLUSIONS; Exercise WMAs in the distribution of the LAD coronary artery are associated with an increased risk of cardiac death and nonfatal MI. This risk is independent of the resting ejection fraction and the extent of WMAs during exercise.

Further data supporting that paclitaxel-associated acute pain syndrome is associated with development of peripheral neuropathy†

Paclitaxel causes an acute pain syndrome (P‐APS), occurring within days after each dose and usually abating within days. Paclitaxel also causes a more classic peripheral neuropathy, which steadily increases in severity with increasing paclitaxel total doses. Little detail is available regarding the natural history of these 2 syndromes, or any relationship between them, although a recent publication does provide natural history data about weekly paclitaxel, supporting an association between the severity of P‐APS and eventual peripheral neuropathy symptoms.

Exercise echocardiography for the prognostic stratification of patients with low pretest probability of coronary artery disease

PURPOSE The aim of this study was to determine whether exercise echocardiography provides incremental data for risk stratification of patients with a low pretest probability of coronary artery disease. PATIENTS AND METHODS The study included patients referred for exercise echocardiography whose probability of coronary artery disease was 25% or less. We calculated an exercise wall motion score index (on a 1-5 scale), an indicator of the extent and severity of exercise-induced abnormalities. The primary outcomes of the study were subsequent cardiac events (cardiac death and nonfatal myocardial infarction). RESULTS We studied 571 men and 1047 women; their mean (+/- SD) age was 55 +/- 13 years. During a median follow-up of 3 years, there were 19 cardiac events (6 cardiac deaths and 13 nonfatal myocardial infarctions); an additional 37 patients underwent coronary revascularization. In a multivariate analysis of clinical, exercise electrocardiographic, and echocardiographic parameters, exercise wall motion score index (hazard ratio [HR] = 2.1 per 0.5 units; 95% confidence interval [CI]: 1.3 to 3.4), and age (HR = 2.0 per decade; 95% CI: 1.2-2.8) were independently associated with the risk of cardiac events. Although exercise echocardiographic variables contributed significantly (P = 0.01) to a model of the risk of adverse events, only 9 (47%) of the 19 patients with cardiac events were identified by an abnormal exercise echocardiogram. CONCLUSION Among patients with low pretest probability of coronary artery disease by clinical criteria, exercise echocardiography identifies some, but not all, patients at risk of future events. Because of the low event rate, routine application of exercise echocardiography in a patient with a low pretest probability does not appear to be cost-effective and therefore cannot be recommended.

Further Data Supporting That Paclitaxel-Associated Acute Pain Syndrome Is Associated With Development of Peripheral Neuropathy North Central Cancer Treatment Group Trial N08C1

Paclitaxel causes an acute pain syndrome (P‐APS), occurring within days after each dose and usually abating within days. Paclitaxel also causes a more classic peripheral neuropathy, which steadily increases in severity with increasing paclitaxel total doses. Little detail is available regarding the natural history of these 2 syndromes, or any relationship between them, although a recent publication does provide natural history data about weekly paclitaxel, supporting an association between the severity of P‐APS and eventual peripheral neuropathy symptoms.

Functional and prognostic significance of exercise-induced ventricular arrhythmias in patients with suspected coronary artery disease

Our aims were to assess (1) the relation between exercise-induced ventricular arrhythmia (VA) and myocardial wall motion abnormalities during exercise echocardiography in patients with suspected coronary artery disease (CAD), and (2) the effect of this relation on outcome. We studied the clinical and prognostic significance of exercise-induced VA in 1,460 patients (mean age 64 +/- 10 years; 867 men) with intermediate pretest probability of CAD and no history of previous myocardial infarction or revascularization who underwent exercise echocardiography. Exercise-induced VA occurred in 146 patients (10%). Compared with patients without VA, those with VA had a greater prevalence of abnormal exercise echocardiographic findings (48% vs 29%, p = 0.001) and ischemia on exercise echocardiography (39% vs 22%, p = 0.001), greater increase in wall motion score index with exercise (0.14 +/- 0.28 vs 0.06 +/- 0.18, p <0.0001), and a greater percentage of abnormal segments with exercise (21 +/- 30% vs 9 +/- 19%, p <0.0001). During follow-up (median 2.7 years), cardiac death and nonfatal myocardial infarction occurred in 36 patients. In multivariate analysis of combined clinical and exercise stress test variables, independent predictors of cardiac events were exercise-induced VA (chi-square 4.7, p = 0.03) and exercise heart rate (chi-square 18, p = 0.0001). The percentage of abnormal myocardial segments with exercise echocardiography was the most powerful predictor of VA (chi-square 31, p = 0.0001) and cardiac events (chi-square 15, p = 0.0001). In patients with suspected CAD, exercise-induced VA is associated with a greater risk of cardiac death and nonfatal myocardial infarction. This risk is attributed to the relation between VA and the extent and severity of left ventricular functional abnormalities with exercise.