To the Editor—Central venous catheter (CVC)–related bloodstream infections (CRBSIs) are clinically important healthcare-associated infections.Reference Magill, O’Leary and Janelle1, Reference Battaglia and Hale2 To reduce the burden of CRBSIs, many countries have implemented national surveillance programs.Reference Hallam, Jackson, Rajgopal and Russell3, 4 Reliable epidemiological data are provided not only by cohort studies but also by randomized controlled trials (RCTs),Reference Parienti, Mongardon and Mégarbane5–Reference Hentrich, Schalk and Schmidt-Hieber7 which are considered the gold standard for assessment of clinically relevant questions.Reference Frieden8 However, patient populations included in RCTs are often highly selected, limiting the generalizability of study results. In contrast, clinical registries can provide useful data on rare conditions in the daily routine that may also be helpful in assessing quality of care. On the other hand, they are limited by substantial confounders and bias.Reference Frieden8
Our aim was to compare epidemiological data on CRBSIs in patients with hematological malignancies derived from a RCT (COAT,Reference Biehl, Huth and Panse6 ClinicalTrials.gov, no. NCT01544686) with data from a prospective registry (SECRECY,Reference Schalk, Hanus, Färber, Fischer and Heidel9 German Clinical Trial Register, no. DRKS00006551). We hypothesized that patients included in a CVC RCT profit from improved CVC care compared to patients under standard clinical care conditions, possibly resulting in different CRBSI rates. Thus, the primary aim of the present analysis was to compare the CRBSI incidences between these groups.
The COAT trial was a RCT carried out from February 2012 to September 2014 in 10 hematology/oncology departments in Germany to compare 2 different types of CVC dressings with respect to the associated CRBSI incidence in neutropenic patients.Reference Biehl, Huth and Panse6 The SECRECY registry began in March 2013 and is an ongoing CRBSI registry,Reference Schalk, Hanus, Färber, Fischer and Heidel9 now in 6 hematology/oncology departments in Germany.Reference Schalk, Toelle and Schulz10 In the present analysis, we included data from patients with nontunneled jugular and subclavian vein CVCs placed ≥1 day in situ. For CRBSI diagnosis, we used the 2012 definitions of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO), considering only definite or probable CRBSIs.Reference Hentrich, Schalk and Schmidt-Hieber7 Because the end points in the COAT trial referred to the 2008 AGIHO/DGHO definitions,Reference Wolf, Leithauser and Maschmeyer11 the underlying data were reassessed, and the more recent definitions were applied to ensure the comparability of the 2 data sets.
According to the aforementioned inclusion criteria, we found 610 cases in the completed COAT trial data set and, as of May 2019, 2,390 cases in the SECRECY registry. In this entire cohort of 3,000 CVCs with 49,542 CVC days, underlying diseases were hematological malignancies and solid tumors in 2,719 (90.6%) and 158 (5.3%) cases, respectively. For a matched-pair analysis, the 610 patients from the COAT trial were matched with those patients from the SECRECY registry with regard to the use of chlorhexidine-coated CVC dressings, sex, and underlying disease with a high risk for CRBSI (ie, acute myeloid leukemia [AML], multiple myeloma, or non-Hodgkin lymphomaReference Schalk, Toelle and Schulz10).
Comparison of continuous variables was conducted using the Mann-Whitney U test, and categorical variables were compared using the Pearson χ2 test or the Fisher exact test, when possible. CRBSI incidences were compared by χ2 test. The Kaplan-Meier method was used for calculating the CRBSI probability over time, and the comparison between both groups was performed using the log-rank test and Cox regression. Two-sided P values <.05 were considered statistically significant. Statistical analyses were carried out using SPSS version 24 statistical software (IBM, Armonk, NY).
Patient and CVC characteristics as well as CRBSI features are shown in Table 1. Patients from the COAT cohort were younger than those from the SECRECY cohort (median, 58 vs 60 years; P < .001). There was a slight male predominance in both groups. COAT included fewer cases of AML than SECRECY (243 of 610 [39.8%] vs 300 of 610 [49.2%]; P = .001) but more cases of multiple myeloma (170 of 610 [27.9%] vs 123 of 610 [20.2%]; P = .002). In the COAT cohort, significantly fewer CVCs were inserted into the jugular vein, compared to the matched SECRECY cohort (41.8% vs 94.3%; P < .001). Although the median duration of CVC placement was significantly longer in the COAT trial than in the SECRECY registry (18 vs 15 days; P < .001), the median time to CRBSI onset was significantly shorter in the COAT cohort (12 vs 14 days; P = .040). We found no difference in the CRBSI rate between the COAT group and the SECRECY group (79 of 610 [13.0%] vs 71 of 610 [11.6%]; P = .542). Furthermore, the proportion of definite and probable CRBSIs was similar in both cohorts (P = .744). Regarding the primary aim of this analysis, the incidence of CRBSIs did not differ significantly with 7.0 CRBSIs per 1,000 CVC days in the COAT trial and 7.3 CRBSIs per 1,000 CVC days in the SECRECY registry (P = .794). Analyzing the CRBSI probability over time (ie, cumulative CRBSI incidence), we also found no significant differences at day 14 between these groups (10.4% in the COAT trail vs 9.6% in the SECRECY registry: hazard ratio, 1.12; 95% confidence interval, 0.74–1.71; P = .583). Finally, we detected no differences in the distribution of pathogen subgroups (P = .142), and coagulase-negative staphylococci were the most common causative pathogens for CRBSIs in both groups.
Table 1. Patient/CVC Characteristics and CRBSI Features
Note. CVC, central venous catheter; CRBSI, central venous catheter-related bloodstream infection; IQR, interquartile range; CRBSI14, cumulative CRBSI probability at day 14; 95% CI, 95% confidence interval.
a Comparison COAT trial data vs matched-pair data from SECRECY registry; all P values are 2-sided.
b Mann-Whitney U test.
c Fisher’s exact test.
d Pearson’s χ2 test.
e Underlying disease with high risk for CRBSI: acute myeloid leukemia, multiple myeloma or non-Hodgkin lymphoma.Reference Schalk, Toelle and Schulz10
f log-rank test.
g χ2 test.
To the best of our knowledge, the present analysis is the first to provide comparative epidemiological data on CRBSIs from a RCT and a registry study in high-risk patients with hematological malignancies. Although limited by some differences in patient and CVC characteristics between both groups, this large matched-pair analysis did not show a reduced CRBSI incidence in patients treated in a RCT compared to patients in routine clinical care implicating a comparable quality of CVC care. Thus, epidemiological data on CRBSIs derived from RCTs may reliably be transferred to real-world settings.
Acknowledgments
The authors thank all COAT investigators involved in the conduct of the trial and all SECRECY investigators for their great support and documentation.
Financial support
No financial support was provided relevant to this article.
Conflicts of interest
D.T. reports grants and personal fees from Gilead, Pfizer, and MSD, grants from Abbvie, Astellas, Celgene, and Jazz outside this work. M.H. has served on advisory boards of Amgen, BMS, Hexal, Janssen, Jazz Pharma, Roche, Sanofi, and Takeda; has served on the speakers’ bureaus of Amgen, BMS, Janssen, Sanofi, and Takeda; and has received travel grants from Amgen, Janssen, and Takeda. B.B. has served at the speaker’s bureau of Astellas, Celgene, Johnson & Johnson, Kite/Gilead, MSD, Novartis, and Takeda; has received research funding from Astellas, Kite/Gilead and MSD; and has consulted for Kite/Gilead, MSD, Novartis, and Takeda. J.P. reports personal fees from Pfizer, Alexion, Apellis, BMS, Celgene, Novartis, Hexal AG, Boehringer Ingelheim, and Chugai Pharma outside the submitted work. M.S.H. reports financial support of educational meetings at the Carl-Thiem-Klinikum Cottbus, Germany, by Janssen-Cilag GmbH, Takeda Pharma Vertrieb GmbH & Co. KG, Novartis Pharma Oncology, Pfizer Pharma GmbH, Roche Pharma AG, Vifor Pharma Deutschland GmbH, and Celgene GmbH. M.J.G.T.V. has served at the speakers’ bureau of Akademie für Infektionsmedizin, Ärztekammer Nordrhein, Astellas Pharma, Basilea, Gilead Sciences, Merck/MSD, Organobalance, and Pfizer; has received research funding from 3M, Evoinik, Glycom, Astellas Pharma, DaVolterra, Gilead Sciences, MaaT Pharma, Merck/MSD, Morphochem, Organobalance, and Seres Therapeutics; and is a consultant to Alb-Fils Kliniken GmbH, Arderypharm, Astellas Pharma, Ferring, DaVolterra, MaaT Pharma, and Merck/MSD. L.M.B. reports lecture honoraria from Astellas and MSD and travel grants from 3M and Gilead. E.S. reports no conflicts of interest relevant to this article.
