Risk of Local Adverse Events Following Cardiac Catheterization by Hemostasis Device Use and Gender

Reports of serious injuries and deaths associated with the use of hemostasis devices1 to the Center for Devices and Radiological Health (CDRH) of the Food and Drug Administration (FDA) provided the impetus for this study. These devices are primarily used to stop bleeding from the femoral artery catheterization site following cardiac diagnostic or interventional procedures. The most commonly used hemostasis devices provide two types of mechanisms for percutaneously controlling bleeding, either deploying sutures to close the femoral puncture site or re-absorbable collagen plugs to temporarily seal the arteriotomy, so as to allow the natural hemostatic process to take place. Studies that have assessed the risks of hemostasis device use compared to no device use (i.e., use of manual compression to stop bleeding) have produced mixed results with regard to the relative risks of serious adverse events (such as hemorrhage). Some have demonstrated no difference between device use versus manual compression controls,2–10 whereas others have shown a greater risk associated with device use11–14 or a lesser risk associated with device use.15,16 It has also been noted in some studies that women are at significantly higher risk than men for serious adverse events associated with the use of hemostasis devices.17–19 Despite the issuance of a public health notification by the FDA in 1999,20 reports of serious injuries and deaths associated with the use of these devices continue to occur with no decrease in frequency. The purpose of this study was to assess the relative risk of serious complications following the use of the two main types of hemostasis device to stop bleeding from the femoral artery following diagnostic and therapeutic cardiac catheterization (as compared with manual compression), and to assess the relative rates of these complications by gender. Methods Source of data. The data used in this study were obtained from the American College of Cardiology-National Cardiovascular Data Registry™ (ACC-NCDR™).21 In 1998, the ACC-NCDR began recruiting United States facilities with cardiac catheterization labs to join their registry program, which involves collecting 142 core data elements needed for measuring the clinical management and outcomes of patients undergoing diagnostic cardiac catheterizations and percutaneous coronary interventions. They recruited institutions for this registry program via general marketing methods, including mass mailings to all catheterization laboratory programs in the United States, scientific session exhibitions and ACC member referral. Although it is voluntary, several states are beginning to require ACC data collection to fulfill state reporting requirements. As of the end of the year 2000, a total of 214 institutions had joined the program. Data quality. ACC-NCDR™ participants submit data quarterly. Prior to analyzing data submitted for any given quarter, Registry staff establish the overall completeness of a participant’s data submission and provide feedback to the participant via a Data Quality Report (DQR). The DQR provides the participant with a confidential analysis of the data submission’s completeness and consistency, and is used by the participant to help prioritize data cleaning efforts and to assess the necessity for resubmission. Upon receipt of the DQR, participants are encouraged to resubmit at any time during the Call for Data period to improve the overall completeness of their data. In order for a data submission to be included in the ACC-NCDR™, each data element must be 95–100% complete. In other words, no element may have more than 5% missing data or the submission will be excluded from the registry’s NCDR averages. Completeness thresholds were chosen for their clinical and structural pertinence. Outcomes and definitions. Seven complications related to the femoral artery catheterization site were assessed. Occlusion and loss of distal pulse were analyzed as one outcome variable because of their similarity. 1) Bleeding: blood loss at the site of arterial or venous access or due to perforation of a traversed artery or vein requiring transfusion and/or prolonging the hospital stay, and/or causing a drop in hemoglobin of greater than 3.0 gm/dl. Bleeding attributable to the vascular site could be retroperitoneal, a local hematoma > 10 cm or external. 2) Occlusion: total obstruction of the artery by thrombus, usually at the site of access, requiring surgical repair. Occlusions may be accompanied by absence of palpable pulse or Doppler. 3) Loss of distal pulse: loss of distal pulse requiring therapy. 4) Dissection: a disruption of an arterial wall resulting in splitting and separation of the intimal (subintimal) layers. 5) Pseudoaneurysm: the occurrence of a disruption and dilation of the arterial wall without identification of the arterial wall layers at the site of the catheter entry demonstrated by arteriography or ultrasound. 6) AV fistula: a connection between the access artery and the accompanying vein that is demonstrated by arteriography or ultrasound and most often characterized by a continuous bruit. 7) Associated death: any death that occurred in a patient in combination with any of the above complications during the same hospitalization. Inclusion/exclusion criteria. Catheterization laboratory discharges for the year 2001 were included in the analysis if the hemostasis method used was either manual compression, a collagen plug device or a suture device (but not both). Excluded from the analysis were: 1) outpatients, as designated by a length of stay of zero days (less than 24 hours), who did not expire on the day of the procedure; 2) any subject for whom information was not complete with regard to gender, type of procedure or type of hemostasis; and 3) admissions were excluded if they lacked information on any of the independent variables used in the regression equations or any of the outcome variables, and cases were excluded from the multivariate analysis if they didn’t include each of the relevant variables. Statistical analysis. We performed step-wise backward multiple logistic regression, using each of the 7 outcome variables individually as the dependent variables, and using age, gender, race (white versus non-white), type of procedure (diagnostic versus interventional cardiac cath), type of hemostasis, body mass index (BMI) and several indices of co-morbidity (New York Heart Association classification, presence of diabetes, hypertension, peripheral vascular disease, acute myocardial infarction, left main coronary artery stenosis, shock, history of congestive heart failure and acute renal failure, emergency versus elective status of the procedure) as independent variables. Results The sample size for the univariate analysis was 166,680, including 113,025 controls, 25,495 uses of the suture device and 28,160 uses of collagen plug devices (Table 1). Serious adverse events were reported in 1.56% of patients; the most common was bleeding (1.13%). Complications were more frequent in women than in men [relative risk (RR) = 2.13; p Literature review of association between adverse outcomes and hemostasis device use. The most important finding of this study was the apparent protective effect of the hemostasis devices. Studies that have assessed complications following the use of hemostasis devices following PTCA have provided mixed results. Silber reviewed 15 such studies involving the use of collagen plug devices and 3 studies involving the use of arterial suture devices.25 The pooled results of these studies showed no significant differences in major complication rates following use of the arterial suture devices compared to manual compression controls, but large differences between subjects and controls using collagen plug devices. The numbers involved in the arterial suture device studies were too small (317 total) to have substantial power. The considerably greater complication rates in subjects using collagen plug devices than in controls could be misleading, since the majority of the difference was accounted for by a single study,11 and the remaining 7 studies4–10 combined demonstrated no statistically significant results. Some studies have found significantly greater complication rates with hemostasis devices than with manual compression.11–14 Three of these studies demonstrated this with respect to the collagen plug devices,11–13 whereas 1 looked only at the suture device.14 Conversely, some other studies have found significantly lower complication rates with hemostasis devices (both suture15 and collagen plug16), than with manual compression. The widely differing results of these studies are perplexing and deserve comment. Studies failing to demonstrate any significant differences were generally quite small, and therefore were lacking in power. The differences between those that demonstrated favorable results for hemostasis devices and those that demonstrated unfavorable results, as compared to manual compression controls, could have been related to the fact that these studies were generally performed in a single institution (in contrast to this study, which utilized 214 different institutions). Some of these institutions may have been characterized by a higher skill level than others in the use of these devices. Possible reasons for our findings of protective effects of hemostasis devices. Why did our study demonstrate an apparent protective effect for hemostasis devices? One possibility is that there are one or more confounding variables that account for this effect. The results of this study do indicate that patients with various serious coexisting cardiovascular problems were at relatively high risk for complications, and that patients were more likely to receive hemostasis devices if they did not have these co-existing problems. Nevertheless, the protective effect remained substantial and highly statistically significant (p = 0.0004), even after controlling for numerous comorbid conditions. However, given that the difference in risk associated with the hemostasis devices and the controls was not very large, there could have been unmeasured factors, connected both with patient risk and with the decision of whether or not to use hemostasis devices, which accounted for that difference. In other words, physicians could have, on average, selectively chosen relatively low-risk patients to receive hemostasis devices. One example of this would be the decision to not use a hemostasis device in situations where an injury occurred to the vessel wall during the procedure, or where a femoral angiogram otherwise demonstrated the puncture site to present a risk for the use of a hemostasis device. This type of situation probably accounted at least in part for the apparent protective effect of hemostasis devices. Another unmeasured confounding variable (for interventional cardiac catheterizations) could have been sheath size. This could have been associated with both an increase in adverse events and in the decision not to use hemostasis devices, thus confounding the results of this analysis. A second possible reason for the apparent protective effect of hemostasis devices shown in this study could have been selective misclassification of or failure to identify adverse events. In order for this to have resulted in an apparent protective effect for the hemostasis devices, proportionately more missed adverse events for device users than for controls would have been necessary. We can think of no plausible reason why this would have happened, but it must be considered a possibility. Lastly, the apparent protective effect could have been real. If so, why did most other studies fail to show this effect? As noted above, due to small sample size, many of them lacked sufficient power to demonstrate differences of the magnitude demonstrated in this study. Others, representing a single institution, may have been somewhat unrepresentative of the general use of these devices. And finally, the differences could be due to the increased skill in the use of these devices with practice. There is some evidence for the existence of such an effect.26,27 Since this study encompassed a later time period than the other studies, the greater experience thereby gained by the participants may have accounted for the better results. Improvements in the devices themselves also may have accounted for the differences. Differential findings for diagnostic versus interventional cardiac catheterization with respect to apparent protective effects of hemostasis devices. The finding that the apparent protective effect of the hemostasis devices with regard to bleeding was evident with respect to diagnostic cardiac catheterization, but not with respect to interventional cardiac catheterization, requires discussion. This finding could mean either that the hemostasis devices provide protection (compared to manual compression controls) when diagnostic catheterization is performed but not when interventional cardiac catheterization is performed, or it could mean that the apparent protective effect when diagnostic cardiac catheterization is performed is not due to the effects of the hemostasis devices, but rather is due to confounding variables associated with diagnostic cardiac catheterization. The former situation could be explained by differences in coagulation status. Anticoagulation is used more in conjunction with interventional than with diagnostic cardiac catheterization, and at least one study showed that activated clotting times (ACT) were greater when hemostasis devices were used, compared with manual compression.13 Therefore, it could be that the longer ACTs associated with interventional cardiac catheterization may have cancelled out the protective effects of the devices with regard to bleeding complications. Finally, it should be noted that this study did not include infection as an outcome, even though infection is a frequent complication of femoral artery catheterization. Infection generally becomes evident after hospital discharge, and this study only examined inpatients. Infection is quite rare following the use of manual compression, but it does occur following the use of both types of hemostasis device assessed in this study. Had we assessed infection in this study, the performance of hemostasis devices would probably have looked less favorable than what we found. We are currently in the process of doing a similar analysis using new ACC-NCTR™ data, which will look at infection. Conclusion. In conclusion, the patients in this study who received hemostasis devices following diagnostic cardiac catheterization (but not following interventional cardiac catheterization) were characterized by a lower risk of serious adverse events relative to non-user controls, especially with respect to hemorrhagic complications and pseudoaneurysm, even after controlling for numerous potential confounding variables. Although the very large number of participating institutions and procedures included in this study ensures that these data are at least reasonably representative of a larger user population, this does not preclude the possibility that these devices could present a risk to patients when used by less experienced operators. While this study cannot exclude the possibility that unmeasured variables connected with patient selection may have been responsible for the apparent protective effect of the hemostasis devices in the study population, overall the devices were found to be safe and effective. Copyright. This material fits the description in the United States Copyright Act of a “United States Government Work,” i.e., all authors are bona fide officers or employees of the United States. The work was prepared as a part of these authors’ official duties as government employees, and therefore is not subject to United States copyright. The article is now freely available for publication, without a copyright notice, and there are no restrictions on its use, now or subsequently, for non-commercial government purposes. Disclaimer. The opinions or assertions presented herein are the private views of the authors and are not to be construed as conveying either an offcial endorsement or criticism by the United States Food and Drug Administration.

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