Risk associated with central catheters for malignant tumor patients: a systematic review and meta-analysis

The risk of venous thrombosis and mortality associated with central catheter (PICC/CICC) for malignant tumor patients is not definite. So, we carried out a systematic review and meta-analysis to evaluate it. Among patients with comparing PICC with CICC, odds ratio (OR) or risk ratio (RR) was calculated with a random effect model meta-analysis. The result of the stratification analysis of 7 studies (PICC vs CICC) supported the theory that CICCs were associated with a decrease in the odds ratio of thrombosis compared with PICCs. 7 of 15 studies provided the information about the compared mortality rate of the patients. The result showed that CICCs were associated with a decrease in the odds ratio of thrombosis compared with PICCs (OR = 0.45, 95% CI:0.32–0.62, p < 0.0001, I2 = 0%,Tau2 = 0.00). Meta-analysis of 8 studies of 2639 patients showed that pharmacological deep vein thrombosis prophylaxis drugs could decrease the risk of mortality of malignant tumor patients with CICCs (RR = 0.58, 95% CI:0.48–0.71, Z = 5.32, p < 0.0001, I2 = 71%). We found that PICCs are associated with a raised risk of deep vein thrombosis, and pharmacological deep vein thrombosis prophylaxis drugs is a beneficial factor in decreasing the incidence of thrombosis, while warfarin may decrease the risk of mortality of malignant tumor patients with CICCs.


INTRODUCTION
Central catheter, including peripherally inserted central catheter (PICC) or central inserted central catheter (CICC), is a device used for many functions among cancer patients, including monitoring haemodynamic indicators and administering intravenous medications, fluids, blood products and parenteral nutrition.The use of it has increased rapidly, especially for PICC.Furthermore, nurse-leading PICC teams have made their use convenient and accessible in many settings [1,2].However, as a foreign inserted object, it is susceptible to deep vein thrombosis and pulmonary embolism which may increase cost, morbidity and mortality [3][4][5].There were plenty of clinical trials about catheter-related infection or thrombosis, and we took a lot of measures to decrease the incidence rate of them among different patients [6][7][8].However, the understanding of risk about central venous catheterrelated side effects is still an important safety question to be resolved, especially for cancer patients as they are prone to be associated with a higher risk of deep vein thrombosis than others [9].To our known, at present, there was no systematic review done to deal with these problems just limited to malignant tumor patients.Therefore, we carried out the systematic review and meta-analysis to further investigate this risk in malignant tumor patients and tried to reveal the relationship between central venous catheter-related side effects and them.We pay our attention mainly to catheter-related venous thrombosis, mortality and mitigation methods, and then compare the risk between PICC and CICC.
15 studies of CICCs with pharmacological deep vein thrombosis prophylaxis data were taken to make further stratification analysis about thrombosis by anticoagulant drugs, divided into warfarin group [24,25,30,31,39,43,50,60], heparin group [37,40,42,44,49,60], and the other thrombolytic group [46,49].The random effect model was tried firstly to deal with the raw data.The forest plot could be seen in Figure 4, and the overall outcome of the analysis were summarized at the bottom of it (OR = 0.67, 95% CI:0.48-0.93,p = 0.02, I 2 = 57%,Tau 2 = 0.24, Figure 4A1).Moderate heterogeneity was noted across studies (I² = 51%, p = 0.02).Harbord's test statistic did not suggest obvious publication bias in funnel plot (Figure 4A2).The Newcastle-Ottawa scale was adopted to evaluate study quality and risk of bias in both comparison and non-comparison studies.Studies with a comparison group were considered as high quality.The subgroup of the other thrombolytic group showed better results in heterogeneity than the other two (OR = 0.27, 95% CI:0.15-0.47,p < 0.0001, I 2 = 0%,Tau 2 = 0.00, Figure 4A1) [46,49].We did not take the fixed model to make further analysis for the existence of heterogeneity.The similar results could be seen when we used a random effect model to assess risk ratio of the data (RR = 0.72, 95% CI:0.56-0.93,Z = 2.48, p = 0.01, I 2 = 51%, Tau 2 = 0.24, Figure 4B).

DISCUSSION
The deep vein thrombosis related to indwelling devices such as PICC and CICC is common, especially in malignant disease [69,70].There are a lot of reports about the relationship between PICCs and venous thromboembolism, but the incidence and risk of it is unclear [71,72].It has been confirmed that venous thromboembolism is a bad signal for the prognosis of malignant disease by plenty of evidence, which is most common in cancer patients [73,74].Thrombosis can be caused by a lot of factors, such as tumor itself, anti-tumor therapy and indwelling devices [69,75].The understanding of risk about central venous catheter-related side effects is still an important safety question to be faced up, especially for cancer patients as they are prone to be associated with a higher risk of deep vein thrombosis than others [9].We have not found a systematic review done to deal with these problems just limited to malignant neoplasms.Therefore, we carried out the systematic review and meta-analysis to further investigate this risk in malignant disease patients and tried to reveal the relationship between central venous catheter-related side effects and malignant neoplasms.
In our meta-analysis, 23 included studies about PICC without a comparison group (n = 5824) were just displayed by a forest plot showing the pooled, unweighted frequency of patients with peripherally inserted central catheter venous thromboembolism (VTE), which can be seen in (Figure 2) [21, 23, 26-29, 33-36, 38, 41, 45, 47, 52-56, 58, 59, 63, 68].For these studies, the unweighted frequency of vein thrombosis was 9.2% (536/5824), which is higher than the former reported result 4.48% (189/4223) related to non-tumor and tumor mixed populations [69].The result of it reveals that PICC-related vein thrombosis is much more prevalent in malignant tumor patients than other populations.It means that the use of PICC in malignant tumor patients would cause a higher risk of developing thrombotic disease.
Though, all kinds of reasons for PICC-related thrombosis have been proposed, such as differences in the anatomical approach to the superior vena cava and more frequent mechanical trauma to the vessel intima in right-handed people, Catheter implantation is the most important causative factor for it [3,76].It would be more likely to cause venous obstruction, when indwelling devices are inserted into peripheral veins.However, if PICCs or CICCs are implanted into larger vessels, the incidence of vein thrombosis would be significantly reduced [55].Tran H reported that PICCs implanted in the internal jugular but arm veins would appeared with a lower incidence of deep vein thrombosis, which supported the suggestion that intimal injury could be associated with PICC-related deep vein thrombosis [55].
Compared to PICCs, CICCs are usually inserted into larger vessels with a lower incidence of vein thrombosis [77].7 studies (n = 2872) reported PICC-related versus CICC or Port-related vein thrombosis outcomes in malignant tumor patients, which were divided into 3 parts for stratification analysis, listed as cancer patients [22,57,61,67], hematological malignancies [51,66], and hematooncology patients [62].The result of the stratification analysis could be seen in (Figure 3), which supported the theory that CICCs were associated with a decrease in the odds ratio of thrombosis compared with PICCs (OR = 0.45, 95% CI:0.32-0.62,p < 0.0001, I 2 = 0%,Tau 2 = 0.00; Figure 3A), especially in cancer patients (OR = 0.30, 95% CI:0.12-0.75,p < 0.05, I 2 = 0%, Tau 2 = 0.00, Figure 3A1) [22,57,61,67], agreed with the former research [77].Similar outcome could also be seen in (Figure 3B), calculated by a fixed effect model.All the results were of statistical significance without obvious heterogeneity.Above the results, we concluded that if the patients appeared with the risk of deep vein thrombosis before catheter insertion, CICC may be a better choice for patients with malignant neoplasms, especially for cancer patients.
As for the heightened risk of deep vein thrombosis, should PICC recipients routinely receive pharmacological DVT prophylaxis in malignant neoplasms?Although more and more clinical trials were put into practice in cancerrelated thrombosis [78], little suitable data for our metaanalysis could be collected in PICC-related area.Instead, 15 studies of CICCs with pharmacological deep vein thrombosis prophylaxis data were collected to make further stratification analysis about thrombosis by anticoagulant drugs, divided into warfarin group [24,25,30,31,39,43,50,60], heparin group [37,40,42,44,49,60], and other thrombolytic group [46,49].Among these studies, warfarin is the most commonly used anticoagulant drug in patients with CICCs [24,25,30,31,39,43,50,60]. We could get the conclusion that anticoagulant drug is a beneficial factor in decreasing the incidence rate of thrombosis.The details of the meta-analysis results were gathered in (Figure 4A) and (Figure 4B), including forest and funnel plot.All the anticoagulant drugs could also been found in other researches with the risk of bleeding among cancer patients [79].We did not take the risk of bleeding for further metaanalysis, because it is not the main object of our study.Furthermore, we did not take the fixed effect model to make further analysis for the existence of heterogeneity.
In conclusion, we found that PICCs are associated with a higher risk of deep vein thrombosis, when compared with CICCs.We could get the conclusion that pharmacological deep vein thrombosis prophylaxis drugs is a beneficial factor in decreasing the incidence of thrombosis and warfarin may decrease the risk of mortality of malignant tumor patients with CICCs.

Search strategy and selection criteria
We took the method called the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) to search materials [10].During the process of searching, we mainly pay our attention to English studies ranged from Jan 01,1970 to June 30,2017 (key words: "Cancers", "Central catheters", "peripherally inserted central catheter", "PICC", "central inserted central catheters ", "CICC", "CVC", "deep vein thrombosis", "pulmonary embolism", "venous thromboembolism", "death", "mortality").Our review includes both independent and industry sponsored studies.We collected the studies in human beings which were presented in   full text, abstract, or poster form.The searching history of PubMed was listed in (supplementary material).The Conference Papers Index which was provided by ProQuest (1982ProQuest ( -2017)), Biosis (1926Biosis ( -2017)), and Scopus (1996-2017), was used to collate conference posters and abstracts.Some ongoing clinical trials were confirmed from American or European clinical trial centers, and other data of interest were gathered from information seeking on the internet and manual access of bibliographies.We had selected four authors independently to confirm their eligibility, and then get agreement together.
Subjects enrolled in the study must meet the following criteria: (1)

Data extraction and validity assessment
The extraction of the data was carried out in accordance with the criteria recommended by the Cochrane Collaboration [11].Treatment groups were confirmed as patients who had PICC or CICC implanted for any indication.We collected the information of the study including the number of patients, population, incidence rate of deep vein thromboses or pulmonary embolisms, indication for central venous duct placement, the position of the central venous duct tip, and use of drugs for prevention of deep vein thrombosis, the survival status of malignant tumor patients.If no useful data was extracted, we would try to get in touch with the author for further information.We divided collected studies into three categories: (1) PICC compared with other infusion methods but CICC; (2) PICC compared with CICC; (3) CICC compared with other infusion methods but PICC.

Assessment of bias risk
Four authors (including two clinicians, a nurse and a statistical analyst) evaluated the risk of central catheters for malignant tumor patients independently.The study quality was judged by Newcastle-Ottawa scale as proposed by the Cochrance Collaboration [12].The meta-analyses mainly checked up venous thrombosis (VT) and mortality rates for all studies.We tried our best to estimate for risk ratio (RR), odds ratio (OR), hazard ratios (HR), and 95% confidence interval (CI) which were derived from Review Manager 5.3, calculated with random effect (RE) or fixed effect (FE) models according to the actual situation of the data.If we could not get the data about mortality events, we would take the inverse variance method to calculated HR. when VT events were not available, a correction factor (0.5) was adopted to revise the RR.The results of effect estimates were considered as statistically significant when P value is less than 0.05.

Main outcome measures
We designated independent researchers to collect the information on venous thrombosis (VT) or pulmonary embolism, survival status and comparison.Deep vein thrombosis was defined as thrombosis related to the deep veins of the arm (brachial, axillary, subclavian, or internal jugular veins) which could be diagnosed by compression ultrasonography, venography, X-ray or CT scan.Survival status included the information about mortality rate of malignant tumor patients and complications affecting the prognosis due to implantation of central catheters but VT.If some information was unclear in the included study, we would get in touch with the study authors to make sure whether the detail of the data was available.If the useful detail was unavailable, the study would be precluded from the analysis [13][14][15][16][17].Where disagreements was found, the corresponding author of the article would deal with the differences.

Statistical analysis
Data of all enrolled studies were summarized with odds ratio (OR) by using the Comprehensive Meta-Analysis software according to whether or not they featured a comparison group.An OR is supposed to be a more conservative estimate and may be more likely to detect a safety signal, as the method by which an OR is calculated provides a point estimate farther from unity than that provided by a HR.We took a random effect model to evaluate most of treatment effects which are different among all studies [18].We also used a fixed effect model occasionally for some analysis when the treatment effects were deemed to be the same and that differences in results were just due to random probability.We collected incidence rate of patients with venous thrombosis from the unit, and then gathered them in non-comparison studies, with variance estimates generated from the enhanced arcsine transformation for data with binomial distributions [19].Cochrane's Q statistic and the I² statistic were taken to deal with the heterogeneity among studies just as recommended by Higgins and colleagues [20].Harbord's test was used to assess publication bias for studies; p values less than 0.05 was deemed to publication bias.We tried to collect all survival data of cancer patients including long-term follow-up data.For chemotherapy studies, an influence plot was generated that shows the estimated OR for mortality if an individual chemotherapy study was precluded from the analysis.All data consolidation and analyses were carried out by Review Manager 5.3.Statistical tests were all two-sided.Effect estimates were deemed statistically significant when p value ≤ 0.05.

Figure 1 :
Figure 1: PRISMA flow diagram of our study.

Figure 2 :
Figure 2: Forest plot and funnel plot showing the pooled, weighted frequency of patients with peripherally inserted central catheter VTE in studies without a comparison group.PICC = peripherally inserted central catheter; CICC = central inserted central catheter; FE = fixed effect; RE = random effect; OR = odds ratio; RR = risk ratio; VTE = venous thromboembolism.

Figure 3 :
Figure 3: (A) Forest plot (A11,RE) and funnel plot (A2,RE) showing risk of venous thromboembolism between peripherally inserted central catheters (PICCs) and central inserted central catheters (CICCs) group.Forest plot showing odds ratio (OR) of development of upper-extremity DVT in patients with peripherally inserted central catheters versus central venous catheters.(B) Forest plot (B1, FE) and funnel plot (B2, FE) showing risk of venous thromboembolism between peripherally inserted central catheters (PICCs) and central inserted central catheters (CICCs) group.Forest plot showing odds ratio (OR) of development of upper-extremity DVT in patients with peripherally inserted central catheters versus central venous catheters.PICC = peripherally inserted central catheter; CICC = central inserted central catheter; FE = fixed effect; RE= random effect; OR = odds ratio; RR = risk ratio; VTE = venous thromboembolism.

Figure 4 :
Figure 4: (A) Forest plot (A1, RE) and funnel plot (A2, RE) showing 15 studies of CICCs with pharmacological deep vein thrombosis prophylaxis data, stratified by anticoagulant drugs Forest plot showing odds ratio (OR) of development of thrombosis in patients with central inserted central catheters (CICCs).(B) Forest plot(B1,RE)and funnel plot (B2,RE) showing 15 studies of CICCs with pharmacological deep vein thrombosis prophylaxis data, stratified by anticoagulant drugs.Forest plot showing risk ratio (RR) of development of thrombosis in patients with central inserted central catheters (CICCs).(C) Forest plot (C1) and funnel plot (C2) showing 15 studies of CICCs with pharmacological deep vein thrombosis prophylaxis data, stratified by patients populations.Forest plot showing odds ratio (OR) of development of thrombosis in patients with central inserted central catheters (CICCs).PICC = peripherally inserted central catheter; CICC = central inserted central catheter; FE= fixed effect; RE = random effect; OR = odds ratio; RR = risk ratio; VTE = venous thromboembolism.

Figure 5 :
Figure 5: (A) Forest plot (A1, RE) and funnel plot (A2, RE) showing 6 of 15 studies with CICCs, stratified by patients populations and pharmacological deep vein thrombosis prophylaxis.Forest plot showing odds ratio (OR) of development of thrombosis in patients with central inserted central catheters (CICCs), stratified by patients populations and pharmacological deep vein thrombosis prophylaxis.(B) Forest plot (B1,RE; B3,FE) and funnel plot (B2,RE; B4,FE) showing 8 studies of 2639 patients with CICCs, stratified by pharmacological deep vein thrombosis prophylaxis.Forest plot showing odds ratio (OR) of development of mortality rate in patients with central inserted central catheters (CICCs).(C) Forest plot (C1, C2) showing 3 studies with CICCs, stratified by the same pharmacological deep vein thrombosis prophylaxis --warfarin.PICC = peripherally inserted central catheter; CICC = central inserted central catheter; FE = fixed effect; RE = random effect; OR = odds ratio; RR = risk ratio; VTE = venous thromboembolism.