Increased Vascular Access Complications in Patients with Renal Dysfunction (Full title below)

Increased Vascular Access Complications in Patients with Renal Dysfunction Undergoing Percutaneous Coronary Procedures Using Arteriotomy Closure Devices

ABSTRACT: Background. Arteriotomy closure device (ACD) use has increased following percutaneous transfemoral coronary procedures (PTCP). However, their safety in patients with chronic kidney disease (CKD) is not known. Therefore, we evaluated the complication rates of ACD among patients with CKD. Methods. Six-hundred ten consecutive patients who underwent PTCP and ACD were retrospectively studied. Patients were grouped according to their creatinine clearance (CrCl in ml/min/1.73 m2) calculated by the Cockcroft-Gault formula using the National Kidney Foundation classification system; Stage I (CrCl ≥ 90); Stage II (60–89); Stage III (30–59); Stage IV (15–29); and Stage V (≤ 15). The primary endpoint was the combined incidence of pseudo-aneurysm, retroperitoneal hematoma, femoral artery thrombosis, surgical vascular repair, and groin infection. Results. Among 610 patients 283 (46%) underwent PCI. The primary endpoint was seen in 66 (10.8%) patients. Univariate predictors of primary outcome were lower CrCl (p Methods We retrospectively studied data from 610 patients who underwent PTCP and ACD placement at our institution between January 1, 2005 and December 31, 2005. Diagnostic coronary catheterization and PTCP were performed according to standard guidelines. Unless contraindicated, all patients undergoing PTCP received aspirin, clopidogrel, weight-adjusted heparin and eptifibatide as needed.15 Weight-adjusted unfractionated heparin dosing was used to achieve an activated clotting time (ACT) using the Hemochron device (International Technidyne, Piscataway, New Jersey) of approximately 200–250 seconds for patients receiving glycoprotein (GP) IIb/IIIa inhibitors and > 300 seconds for all other patients.16,17 Patients in this study received GP IIb/IIIa receptor inhibitors according to usual protocol with eptifibatide including renal doses. Post-PCI patients were treated with aspirin (81 mg to 325 mg/day) and clopidogrel (300 or 600 mg as a loading dose followed by 75 mg/day) if stents were placed. The cardiologist performing the procedure chose the method of arterial access management and type of ACD used. The ACD placement was performed by physicians trained in their use. The ACD was placed only after a femoral angiogram was performed via the arterial sheath. Patients with inappropriate vessel size (Estimation of Glomerular Filtration Rate (eGFR) The patient’s creatinine Clearance (CrCl) in mL/min was calculated using the Cockcroft-Gault formula for eGFR estimation: (140 - age) x (weight) x (0.85 if female) / (72 x SCr). This formula has been appropriately validated and accurately predicts basal eGFR utilizing serum creatinine and the patient’s body weight.19–21 The kidney disease outcome quality initiative in 2001 developed guidelines that defined CKD as structural or functional abnormalities of the kidney, demonstrated most often by persistent albuminuria, with or without decreased eGFR ( 6 cm or access site bleeding and/or (> 3g Hgb drop or > 10% drop in hematocrit) requiring transfusion or retroperitoneal bleeding confirmed on CT scan, including those that prolonged hospitalization and that required surgical intervention. Bleeding complications were defined as per the TIMI criteria. 2. Infection. Erythema, swelling and purulent drainage from the access site with or without systemic manifestations of fever and bacteremia. An ID specialist was consulted on all the patients who had infection and IV antibiotics were given. 3. Dissection or femoral artery thrombosis. Loss of peripheral pulses and thrombosis or dissection diagnosed by duplex ultrasound and requiring intervention. 4. Device failure. Any circumstance in which the device did not achieve hemostasis. Statistical analysis. Statistical analysis was performed using a standard statistical software package (SPSS for Windows, version 16; SPSS, Inc., Chicago, Illinois). Continuous variables were expressed as the mean ± standard deviation. Normally distributed variables were compared by ANOVA. Categorical variables were expressed as a percentage of the total sample and compared using the chi-square test or Fischer’s exact test when appropriate. Risk factors for complications were expressed by univariate odds ratios. Multivariate logistic regression analysis was performed to determine the independent predictors for the development of complications. A multivariate logistic regression model including age, gender, diabetes, CKD stage, closure type and smoking was used. A p-value of Results Tables 1 and 2 describe the baseline clinical and procedural characteristics of the study population classified according to the eGFR. Among 610 patients studied, 105 (17.2%) were in Stage I, 260 (42.6%) Stage II, 192 (31.4%) Stage III, 36 (5.9%) Stage IV, and 17 (2.8%) in Stage V kidney function. Two hundred eighty-three patients (46%) underwent interventional procedures, and 522 (85%) had a collagen device placed. Two hundred forty-five patients (67%) had CrCl 60 ml/min (55% vs. 44%; p = 0.07). There were no significant differences among the groups in regard to smoking, body mass index (BMI) and presence of peripheral vascular disease (PVD). There was a trend toward a decrease in platelet counts as the renal function declined, with Stage ≥ IV patients having platelets 60 mL/min who underwent diagnostic or interventional procedures, and Groups C and D were patients with CrCl Discussion The aim of this study was to define the association between severity of CKD and the rate of vascular access complications in patients undergoing PTCP using ACD. The results of our study show an overall complication rate of 10.8%, which is higher than that in previous studies. This discrepancy is most likely due to high percentage of CKD patients, with 40% of the study population having CKD ≥ III. In a recently published study from the Mayo Clinic of 17,901 patients who underwent PCI, complication rates ranged from 3.5–8.4%. However, patients with moderate-to-severe renal impairment were underrepresented, comprising only 3.5% of the entire study population.24 In our study, there was a significant relationship between renal dysfunction and the incidence of vascular complications following ACD, mainly due to higher bleeding and infection rates in those with severe renal dysfunction reaching up to 20% in patients with CrCl Potential Explanation of Our Findings As in other studies, bleeding was the most frequent complication noted in our study population, with an incidence rate of 6%. Further analysis revealed an increasing incidence of bleeding complications as the stage of CKD increased, with a complication rate of 30% in patients with Stage ≥ III. This observation is likely a result of uremia-induced platelet dysfunction, which is commonly seen in patients with advanced renal impairment. The platelet dysfunction characteristic of uremia is multifaceted. Platelet count is usually within the normal range or slightly low in patients with uremia. It has been suggested that these patients have a complex platelet dysfunction and an abnormal platelet-endothelial vessel wall interaction.26 Radioligand studies have indicated that the binding of fibrinogen to ADP-stimulated platelets in uremic media is impaired. Notably, the ability of the vessel wall to generate the potent antiaggregatory substance prostacyclin (prostaglandin I2) increases in uremia; moreover, endothelial cells seem to generate an abnormal complex of coagulation factor VIII (antihemophilic factor) and Von Willebrand factor (vWF). Finally, the largest polymers of vWF, which are primarily responsible for the adhesion process, are deficient in patients with uremia, although the serum level of vWF in these patients is usually high or within the normal range.26,27 Infectious complications are an uncommon but serious complication of ACD use, with a reported incidence of 0– 5.1%.28,31 Infectious complications were seen in 11 patients (1.6%) in our study and similar to the trend seen with bleeding complication, incidence rates increased significantly as the renal function declined. Bleeding complication at the access site and the presence of foreign material in the intravascular space and arterial wall likely serve as a nidus for subsequent infection. Uremia causes immune dysfunction and increased susceptibility to infection through a variety of mechanisms.32,33 Patients on hemodialysis often display compromised neutrophil and T-cell function as well as diminished antibody production. The diminished neutrophil function may in part be due to the use of bioincompatible dialysis membranes, which result in impaired adherence and attenuated responses to phagocytic stimuli. In addition to these mechanisms, some of the immune deficits may also be explained by the presence of elevated endogenous glucocorticoids present in patients with renal impairment.32,33 Neutrophil impairment is also associated with diabetes, a major cause of CKD, and correlates directly to the level of hyperglycemia. Moreover, diabetics often have poor peripheral circulation that often leads to skin ulceration and diminished delivery of neutrophils to sites of microbial entry. Diabetes was prevalent in 70% of our patients with Stage V kidney function, but was not shown statistically to be a multivariate risk factor for vascular complications. Currently, there are no standardized guidelines for prevention of access-site infections. Some experts have recommended prophylactic use of antibiotics before ACD placement in high-risk patients, especially those with diabetes mellitus,29,30,34,35 however, no prospective clinical trials are available to assess the effectiveness of this strategy. Arterial dissections were seen in 10 (1.6%), femoral artery thrombosis in 5 (0.8%), and device failure in 3 (0.5%) of our study patients. These complications have been published in prior studies, but have very low incidence rates and have shown no statistically significant differences between the types of devices used or between any other pre, intra- and post-procedural characteristics.36–38 This finding was similar to the results of our study. Previous Studies Multiple studies and three major meta-analyses have investigated the complication rates post-ACD use compared to mechanical compression.13,14,39–48 Despite the differences in the study population and design, the following conclusions can be drawn. Among patients undergoing diagnostic cardiac catheterization, there is a 0.5–1.7% rate of vascular complications and this risk is not consistently increased or decreased by ACD usage across all studies.18 Among patients undergoing interventional procedures, there is a 0.8–5.5% rate of heterogeneously defined vascular complications, and there are no clear data to indicate increased risk in the ACD groups, with the exception of the Vaso-Seal device.18 These studies identified older age, female gender, lower weight, smaller body surface area and renal failure to confer increased risk of vascular complications, but there are no studies specifically evaluating the role of kidney function on complication rates after ACD placement.37–40 Study limitations. This was a retrospective study and is subject to the limitations of this design. Also, the single-center experience limits the generalizability of these findings beyond a sample of patients with similar medical conditions and treated with similar medical protocols. Reporting biases because of variations in endpoint definitions may have influenced the apparent higher incidence of complications, but are unlikely to have biased the results. This study outlined in-hospital outcomes; however, the possibility of late complications cannot be extrapolated from our data. The more severe CKD groups had relatively small numbers of patients. Also, we have no comparison to nonfemoral artery access, but these patients with severe renal dysfunction would not be good candidates for radial or brachial artery access due to the need for hemodialysis fistula creation in their arms should they need permanent hemodialysis. Finally, there was no comparison to the manual compression group. Conclusions Our results suggest that patients with baseline CKD undergoing PTCP and ACD placement should be closely monitored for complications, especially infection and hematoma formation. The risk category can also be further stratified based on the degree of renal function with Stage IV CKD and above being at the highest risk for vascular complications. Our findings also reemphasize the importance of aseptic techniques and judicious use of prophylactic antibiotics. There is a need for large-scale randomized studies of these devices to definitively address safety concerns and also to further identify predictors of complications. Data on predictors of complications can play a pivotal role in prevention, early detection and proper management in these high-risk patients. From the aDivision of Cardiology, St. Luke’s and Roosevelt Hospital Center, Columbia University College of Physicians & Surgeons, bLenox Hill Hospital, and cGood Samaritan Hospital, New York, New York. The authors report no conflicts of interest regarding the content herein. Manuscript submitted March 9, 2009, provisional acceptance given April 10, 2009, final version accepted September 25, 2009. Address for correspondence: Mun K. Hong, MD, Director, Cardiac Catheterization Laboratory and Interventional Cardiology, St. Luke’s-Roosevelt Hospital Center, 1111 Amsterdam Avenue, New York, NY 10025. E-mail: MKHong@Chpnet.org

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