Association of Early Postoperative Pain Trajectories With Longer-term Pain Outcome After Primary Total Knee Arthroplasty.

Importance: Studies to date have not comprehensively examined pain experience after total knee arthroplasty (TKA). Discrete patterns of pain in this period might be associated with pain outcomes at 6 to 12 months after TKA. Objectives: To examine patterns of individual post-TKA pain trajectories and to assess their independent associations with longer-term pain outcome after TKA. Design, Setting, and Participants: This prospective cohort study combined data from a national US TKA cohort with ancillary pain severity data at 2 weeks and 8 weeks after the index TKA using a numeric rating scale. All participants received primary, unilateral TKA within the Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement (FORCE-TJR) national network of community sites in 22 states or at the lead site (University of Massachusetts Medical School). Participants had a date of surgery between May 1, 2013, and December 1, 2014. The data analysis was performed between January 13, 2015, and July 5, 2016. Exposures: Pain trajectories in the postoperative period (8 weeks). Main Outcomes and Measures: Index knee pain at 6 months after TKA using the Knee Injury and Osteoarthritis Outcome Score (KOOS) pain scale. Group-based trajectory methods examined the presence of pain trajectories in the postoperative period (8 weeks) and assessed whether trajectories were independently associated with longer-term pain (6 months). Results: The cohort included 659 patients who underwent primary TKA with complete data at 4 points (preoperative, 2 weeks, 8 weeks, and 26 weeks). Their mean (SD) age was 67.1 (8.0) years, 64.5% (425 of 659) were female, the mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 30.77 (5.66), 94.5% (613 of 649) were white, and the mean (SD) preoperative 36-Item Short Form Health Survey physical component summary and mental component summary scores were 34.1 (8.2) and 53.8 (11.4), respectively. Two pain trajectory subgroups were identified at 8 weeks after TKA: patients who experienced fast pain relief in the first 8 weeks after TKA (fast pain responders, composing 72.4% [477 of 659] of the sample) and patients who did not (slow pain responders, composing 27.6% [182 of 659] of the sample). After adjusting for patient factors, the pain trajectory at 8 weeks after TKA was independently associated with the mean KOOS pain score at 6 months, with a between-trajectory difference of -11.3 (95% CI, -13.9 to -8.7). Conclusions and Relevance: The trajectory among slow pain responders at 8 weeks after surgery was independently associated with improved but greater persistent index knee pain at 6 months after TKA compared with that among fast pain responders. Early identification of patients with a trajectory of slow pain response at 8 weeks after TKA may offer an opportunity for interventions in the perioperative period to potentially improve the long-term pain outcomes after TKA.

A Comparative Study of Longitudinal Toxicities of Cytotoxic Drugs, Molecularly Targeted Agents, Immunomodulatory Drugs, and Cancer Vaccines.

Little is known about the toxicity of various therapeutics for cancer over time because randomized controlled clinical trials that compare several treatments are limited. In this study, we focused on the toxicities most frequently discussed, which are investigations (lab abnormalities), gastrointestinal disorders, skin and subcutaneous tissue disorders, and cardiac disorders, and compared their longitudinal toxicity data among four types of cancer therapeutics. In total, 28,235 patients who were enrolled into 772 early-phase trials to evaluate the monotherapies of cytotoxic drugs, molecularly targeted agents, immunomodulatory drugs, or cancer vaccines were evaluated. For each toxicity, we compared their grade prevalence, mean grade at each cycle, and time to toxicity occurrence and identified the potential underlying similarities and differences of longitudinal toxicities among the four cancer treatment types. Our results will further help in understanding the profile of cancer therapeutic toxicities and their impact on oncology treatment in practice.

Longitudinal adverse event assessment in oncology clinical trials: the Toxicity over Time (ToxT) analysis of Alliance trials NCCTG N9741 and 979254.

BACKGROUND: Traditional methods of reporting adverse events in clinical trials are inadequate for modern cancer treatments with chronic administration. Conventional analysis and display of maximum grade adverse events do not capture toxicity profiles that evolve over time or longer lasting, lower grade toxic effects; we aimed to address this shortcoming in this study. METHODS: We developed an analytic approach and standardised, comprehensive format, the Toxicity over Time (ToxT) approach, which combines graphs and adverse event tabular displays with multiple longitudinal statistical techniques into a readily applicable method to study toxic effects. Plots visualising summary statistics or individual patient data over discrete timepoints were combined with statistical methods including the following longitudinal techniques: repeated measures models that describe the changes in adverse events across all cycles of treatment; time-to-event analyses of first and worst grade toxicity; and area under the curve (AUC) analyses summarising adverse event profiles over the entire course of a study, including chronic low-grade events. We applied ToxT analysis to adverse event data from two completed North Central Cancer Treatment Group (NCCTG/Alliance) trials: N9741 (NCT00003594), in which different combinations of oxaliplatin, 5-fluorouracil, and irinotecan were investigated for metastatic colorectal cancer, and 979254, in which survivors of breast cancer were given venlafaxine or placebo for control of hot flashes. FINDINGS: In trial NCCTG 979254 there was a higher incidence of late-occurring dry mouth in patients who were given venlafaxine than in those given placebo (week 1 [baseline]: 13% [six incidence in 48 patients, SD 5] vs 22% [11/49, SD 6]; p=0·20; week 5: 49% [24/49, 7] vs 2% [1/46, 2]; p<0·0001). In trial NCCTG N9741 there was an increased incidence of early nausea for patients given irinotecan plus oxaliplatin (IROX) compared with those given 5-fluorouracil plus oxaliplatin (FOLFOX; cycle 1 mean grade nausea 1·1 [SD 1·0] vs 0·6 [0·7]; p<0·0001). Event charts showed earlier occurrences of higher grades of diarrhoea for patients given IROX compared with those given FOLFOX, and the AUC analysis shows a higher magnitude of diarrhoea consistently over time throughout the study in patients given IROX versus those given FOLFOX (mean AUC 4·2 [SD 5·2] vs 2·9 [4·2]; p<0·0001). INTERPRETATION: The ToxT analytical approach incorporates the dimension of time into adverse event assessment and offers a more comprehensive depiction of toxic effects than present methods. With new, continuously administered targeted agents, immunotherapy, and maintenance regimens, these improved longitudinal analyses are directly relevant to patients and are crucial in cancer clinical trials. FUNDING: National Cancer Institute of the National Institutes of Health and the Mayo Comprehensive Cancer Center.

Common long-term complications of adult congenital heart disease: avoid falling in a H.E.A.P.

Advances in cardiology and cardiac surgery have transformed the outlook for patients with congenital heart disease (CHD) so that currently 85% of neonates with CHD survive into adult life. Although early surgery has transformed the outcome of these patients, it has not been curative. Heart failure, endocarditis, arrhythmias and pulmonary hypertension are the most common long term complications of adults with CHD. Adults with CHD benefit from tertiary expert care and early recognition of long-term complications and timely management are essential. However, it is as important that primary care physicians and general adult cardiologists are able to recognise the signs and symptoms of such complications, raise the alarm, referring patients early to specialist adult congenital heart disease (ACHD) care, and provide initial care. In this paper, we provide an overview of the most commonly encountered long-term complications in ACHD and describe current state of the art management as provided in tertiary specialist centres.