July 2019

Synopsis: Drug-coated endovascular technology (i.e., drug-coated balloons [DCB] and drug-eluting stents [DES]) has gained widespread usage in the management of femoropopliteal peripheral arterial disease. Paclitaxel is currently the drug of choice in this clinical context, as data suggests that it improves patency rates by inhibiting post-angioplasty neointimal hyperplasia associated with early vessel restenosis. Indeed, as a result of the strength of this data, the FDA has approved multiple devices for treatment of the femoropopliteal segment. However, recent studies have questioned the safety of this treatment modality, including the INPACT-DEEP study (study of IN.PACT Drug-Eluting Balloon vs. Standard Balloon Angioplasty for the Treatment of Below the Knee Critical Limb Ischemia) that showed higher rates of amputation in the paclitaxel DCB and DES groups, and two randomized controlled trials (RCTs) with long-term follow up suggesting increased late patient mortality in the paclitaxel groups.

In the recent publication by Katsanos et al., the investigators perfomed a meta-analysis of 28 RCTs made up of 4,663 patients with femoropopliteal disease to evaluate the long-term outcomes of drug-coated endovascular technologies. The primary safety measure was all-cause patient mortality. The study population primarily included those with intermittent claudication (89% claudicants, with the remaining 11% critical limb ischemia). At 1-year follow up, the incidence of all-cause mortality in patients treated with paclitaxel-coated devices versus traditional non-drug coated devices was similar (2.3% vs 2.3%, crude risk of death; RR, 1.08; 95% confidence interval [CI], 0.72–1.61). However, at two years (12 RCTs with 2,316 patients) the incidence of all-cause mortality was significantly increased in the paclitaxel group (7.2% vs 3.8% crude risk of death; RR, 1.68; 95% CI, 1.15–2.47), and this trend was found to persist out to five years as well (14.7% vs 8.1% crude risk of death; RR, 1.93; 95% CI, 1.27–2.93; with data from 3 RCTs, n=863). Lastly, meta-regression analysis confirmed a significant relationship between exposure to paclitaxel and the absolute risk of death. 

The primary weaknesses of this study are the lack of robust long-term data as reflected by the variability of the risk estimate of mortality, the absence of patient-level data (specifically, the cause-of-death of patients to help define any causal links with paclitaxel use), and the heterogeneity of studies (e.g., grouping together DES and DCBs) which raises questions about the validity of conclusions based on their pooled data. 

These findings have sparked a strong response by the vascular community, leading to a re-assessment of results by the relevant device companies and the FDA. As a temporizing measure, the FDA recently released a statement to healthcare providers recommending “alternative treatment options” for most patients until additional analysis had been performed. Nevertheless, they ultimately left the decision to the discretion of the provider, dependent on individual circumstances and open dialogue of the risks and benefits with their patients. Lastly, they emphasized the importance of continued monitoring of patients treated with these devices and the diligent reporting of outcomes while they undertake a more thorough review of past and present data.  

Synopsis: The use of minimally invasive surgery has become increasingly popular in the East, where it has become standard for distal gastrectomies for early gastric cancers. The CLASS-01 trial was a Chinese multicenter RCT to evaluate laparoscopic vs. open distal gastrectomy with D2 lymphadenectomy for locally advanced (≥T2N0) gastric cancer. In a non-inferiority trial of 1056 patients (528 in each arm), 3-year DFS (laparoscopic: 76.5% vs. open: 77.8%) and 3-year OS (laparoscopic: 83.1% vs. open: 85.2%) were not significantly difference between cohorts. Given previously published short-term data that demonstrated equivalent morbidity, faster postoperative recovery, and comparable lymph node yield and rates of positive margin resection, the authors conclude that laparoscopic distal gastrectomy is the preferred technique for locally advanced distal gastric adenocarcinoma. The trial is quite large and the data of high quality, but there are several issues to note. Firstly, almost one-third of the entire cohort was overstaged at time of surgery and were found to be early-stage, not locally advanced cancer. In a post-hoc analysis, the differences in 3-year DFS between the laparoscopic and open distal gastrectomy groups increased with tumor stage, such that there was a nonsignificant benefit of open gastrectomy for pathologic stage III patients -- although statistical significance was not reached in any of the stage subgroups. Finally, the applicability of these data to the U.S. population may be limited in most, or all, centers. Participation in the trial was limited to institutions with an annual volume of 300 gastrectomies and to surgeons who had performed at least 50 distal gastrectomies with D2 lymphadenectomy. This volume may not be reached by any single U.S. institution. 

Synopsis: Despite lack of efficacy data, antimicrobial prophylaxis for surgical site infection (SSI) prevention is often continued for extended periods of time after incision closure. The harms associated with this practice have not been well characterized. In this multicenter, retrospective cohort study, all patients within the VA healthcare system who underwent cardiac, orthopedic joint replacement, colorectal and vascular procedures from 10/1/2008 – 9/30/2013 were included to assess the effect of duration and type of antimicrobial prophylaxis on rates of SSI, acute kidney injury (AKI) and Clostridium difficile infections.

A total of 79,058 patients were included in the study. After stratified by type of surgery and adjustment was made for age, sex, race, diabetes, smoking, ASA score >2, MRSA colonization, mupirocin, type of prophylaxis, and facility factors, SSI was not associated with duration of prophylaxis. 

For each additional day of prophylaxis, adjusted odds ratio (aOR) of AKI increased. Combination regimens (ex. vancomycin + β-lactam) were associated with an additional increased risk of AKI compared to single-agent regimens. 

For each additional day of prophylaxis, adjusted odd ratio of C. difficile infection increased. 

In addition, receipt of vancomycin was a significant risk factor for AKI (cardiac procedure: aOR, 1.17; 95% CI, 1.10-1.25; noncardiac procedure: aOR, 1.21; 95% CI, 1.13-1.30).

Clinical Takeaway:
Increased duration of antimicrobial prophylaxis is associated with higher odds of both AKI and C. difficile infection, in a duration-dependent manner. Extended duration of prophylaxis does not lead to additional reduction in SSI.

Further Reading on Appropriate Use of Antibiotics:

• Sawyer RG, Claridge JA, Nathens AB, et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med. 2015;372:1996-2005.

Randomized trial of 518 patients with complicated intra-abdominal infections after adequate source control which demonstrated equivalent outcomes for short-course of antibiotics (approximately 4 days) vs. longer duration (approximately 8 days).

• Dragan V, Wei Y, Elligsen M, et al. Prophylactic antimicrobial therapy for acute aspiration pneumonitis. Clinical Infectious Diseases. 2018;67(4):513-518.

Retrospective cohort study of 200 patient demonstrating that prophylactic antimicrobial therapy for acute aspiration pneumonitis is not associated with reduction in mortality or reduced need for ICU care, but is associated with more frequent escalation of antibiotics and fewer antibiotic-free days.

• Yahav D, Francheschini E, Koppel F, et al. Seven versus 14 days of antibiotic therapy for uncomplicated gram-negative bacteremia: A noninferiority randomized controlled trial, Clinical Infectious Diseases. ciy1054, https://doi-org.proxy.library.upenn.edu/10.1093/cid/ciy1054

A randomized, multicenter, open-label, non-inferiority trial of patients hospitalized with gram-negative bacteremia who achieved clinical stability before day 7 which showed that an antibiotic course of 7 days was non-inferior to 14 days.