2 Minute Medicine Rewind March 10 – 17, 2014

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In this section, we will highlight the key high-impact studies, updates, and analyses published in medicine during the past week.

Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia

Idelalisib, a phosphatidylinositol 3-kinase inhibitor, showed promising clinical activity and low toxicity during treatment of relapsed CLL in phase 1 studies in elderly patients with comorbid conditions, who often cannot tolerate standard treatments. In this randomized, double-blinded, phase 3 study, 220 elderly patients with relapsing CLL and contraindications to standard therapy (myelotoxicity caused by prior therapy, poor renal function, or other serious coexisting illness) were randomized to treatment with rituximab and idelalisib  or rituximab and placebo to study the effect on progression-free survival. Progression-free survival was much higher in the idelalisib group than the placebo group at 24 weeks (93% vs 46%, adjusted HR 0.15, 95% CI 0.08-0.28), and the study was stopped early due to efficacy. Overall survival was higher in the idelalisib group compared to placebo (92% vs 80% at 12 months, adjusted HR 0.2, 95% CI 0.09-0.86), as were overall response rates (80% vs 13%, OR 29.92, p<0.001). The idelalisib group reported more diarrhea and rash than the control group, as well as more frequent AST/ALT elevations, but the rates of study-drug discontinuation due to adverse events were similar (8% vs 10% in the placebo group). The combination of idelalisib and rituximab shows promising short-term efficacy and an acceptable safety profile for frail, elderly patients with relapsed CLL.

Comparison of 2 Transvaginal Surgical Approaches and Perioperative Behavioral Therapy for Apical Vaginal Prolapse

The only definitive treatment for pelvic organ prolapse is surgery, however no evidence exists comparing the efficacy of the two most common surgical procedures, sacrospinous ligament fixation (SSLF) and uterosacral ligament suspension (ULS). In this 2×2 randomized controlled trial, 374 women undergoing surgery for pelvic organ prolapse and stress urinary incontinence were randomized to SSLF or ULS, and to pelvic floor muscle training or usual care perioperatively in order to study the effect on anatomic and symptomatic improvement at 2 years. There was no significant difference in surgical success between participants who underwent ULS (60.5%) vs SSLF (59.2%) (based on a composite of anatomic measures, vaginal bulge symptoms, and necessity of retreatment at 2 years) (adjusted OR 0.9, 95% CI 0.6-1.5), though more women in the SSLF group reported vaginal bulge symptoms at 6 and 12 months post-op. Unexpectedly, women randomized to pelvic floor muscle training and ULS were more likely to develop apical descent than those who underwent usual care. Overall, perioperative pelvic floor muscle training did not improve symptomatic outcomes at 6 months or 24 months when compared to usual care (p=.61). SSLF and ULS have comparable success rates 2 years after surgery for pelvic organ prolapse, and perioperative pelvic floor training did not improve outcomes for patients undergoing these procedures.

Clinical Interpretation and Implications of Whole-Genome Sequencing

As the cost of sequencing the entire genome falls, it is important to consider the clinical implications of whole-genome sequencing (WGS) as opposed to more targeted sequencing based on clinical presentation. In this small exploratory study, investigators sequenced the entire genomes of 12 healthy volunteers using 2 commercially available sequencing platforms to determine genome coverage, platform concordance, and agreement on clinical significance of various disease-risk variants. Depending on sequencing platform, 10% to 19% of genes associated with inherited diseases were not sufficiently covered (>10 reads) to allow for accurate assessment of individual genetic variation, though there was a high degree of concordance (99%) between the two platforms for common genetic variants. WGS resulted in identification of 90 to 127 variants per participant requiring further literature review, with only moderate interrater agreement on variant pathogenicity (Gross k 0.52, 95% CI 0.40-0.64) and fair agreement on the need for clinical follow-up of the results of WGS (Fleiss k 0.24, p<0.001).  Only one rare, expected pathogenic variant (in BRCA1) was identified among 9 patients, though at least 1 previously disease-associated variant was identified in each of the 12 patients. WGS also identified a median of 13 reportable variants with implications for carrier status per participant, most (median 9) of which were of uncertain significance. This study illustrates that despite advances in WGS technology, clinical implications of WGS are still limited by incomplete disease gene coverage, the large degree of variants of unknown significance, and the resource-intensiveness required to interpret the results of WGS.

Introduction of Surgical Safety Checklists in Ontario, Canada

Introduction of surgical safety checklists, when adopted voluntarily by hospitals, has been shown to significantly reduce the rate of surgical complications and death, however there are mixed results on the efficacy of mandatory checklist adoption. In this retrospective analysis, investigators compared rates of surgical mortality and complications in 3-month periods ending 3 months before and starting 3 months after the mandatory introduction of surgical checklists at 101 hospitals in Ontario. They found no significant change in the adjusted risk of post-operative 30-day mortality in the periods before and after implementation of the checklists across all hospitals (0.71% before implementation vs 0.65% after, p=.07),nor within individual hospitals. There was no difference in the adjusted risk of surgical complications between the two groups overall (3.86% before vs 3.82% after, p=.53), though some sites had a significant reduction in surgical complications while others had a significant increase. The risk of unplanned return to the operating room decreased after introduction of the checklist (p<.001), but there was an increased risk of deep venous thrombosis (from 0.03% to 0.07%, p<.001) and ventilator use (from 0.08% to 0.12%, p=.007). The lack of improvement in surgical mortality and complications after the introduction of surgical checklists was unexpected given prior studies, and it is unclear whether this is due the retrospective nature of the analysis, implementation of a single checklist rather than multiple safety changes, or a truly limited effectiveness of surgical checklists on patient safety in the community setting.

Randomized Clinical Trial of Hydrocodone/Acetaminophen Versus Codeine/Acetaminophen in the Treatment of Acute Extremity Pain After Emergency Department Discharge

The recent Food and Drug Administration recommendation to reclassify hydrocodone from Schedule III to Schedule II will require a change in how often physicians prescribe hydrocodone/acetaminophen, the most popularly prescribed opioid analgesic. In this randomized, double-blind trial, 240 Emergency Department patients with acute onset (within 7 days of presentation) extremity pain with planned discharge for outpatient management were assigned to receive a 3-day course of either hydrocodone/acetaminophen (5/500mg) or codeine/acetaminophen (30/300mg) to study the effect on reported analgesic efficacy, side-effect profile, and patient satisfaction. During a follow-up phone call the day after discharge, the study found no difference in analgesic effect between the two groups: patients’ reported pain score on average went from 7.6 in both groups to 3.6 (SD 2.8) in the hydrocodone/acetaminophen group and 4.1 (SD 2.9) in the codeine/acetaminophen group (absolute difference -0.4, 95%CI -1.3 to 0.4). There was no significant difference in side-effect profile or patient satisfaction. This study showed no difference in the efficacy of hydrocodone, a drug with higher potential for abuse, and codeine, for acute pain relief.

Rising Opioid Prescribing in Adult U.S. Emergency Department Visits: 2001-2010

Prescription of opioid analgesics has increased nationally over the past decade, as have rates of opioid abuse and overdose. In this retrospective study, researchers reviewed trends in analgesic prescriptions during emergency department (ED) visitsby examining data from the National Hospital Ambulatory Care Survey (NHAMCS) from 2001-2010. Opioid analgesics were prescribed in 49% more ED visits in 2010 (31.0% of visits) than in 2001 (20.8%) (absolute increase 10.2%, 95%CI 7.0%-13.4%), though there was only a 4% absolute increase in pain-related complaints (47% to 51%). There was the greatest increase in oxycodone (2.2% in 2005 to 3.9% in 2010, relative increase of 79.6%) and hydrocodone (7.9% to 9.1%, relative increase 15.4%) prescriptions at discharge. There was no concomitant change in the prescription of codeine non-opioid analgesics at discharge. The increase in opioid prescribing was significant across all age groups, races, genders, and methods of payment, and the disparity in opioid prescribing between blacks and whites has decreased, though black patients continue to be less likely to prescribed opioids. This study shows a trend in more aggressive pain management during ED visits from 2001 to 2010, which must be examined carefully in relation to the simultaneous rise in opioid abuse.

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