Risk of Local Adverse Events following Cardiac Catheterization
by Hemostasis Device Use — Phase II

Reports to the Center for Devices and Radiological Health (CDRH) of the FDA regarding serious injuries and deaths associated with the use of vascular hemostasis devices¹ provided the impetus for this study. These devices are used primarily 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 vascular 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,^2–13 whereas others have shown a greater risk associated with device use^14–18 or a lesser risk associated with device use.^19–20 Despite the issuance of a public health notification by the FDA in 1999,²¹ reports of serious injuries and deaths associated with the use of these devices continued to occur without decrease in frequency. Consequently, the FDA conducted a study (Phase I), in collaboration with the American College of Cardiology (ACC), to assess the relative risk of serious complications following the use of the two main types of vascular hemostasis devices 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.²² That study, which included 2001 data from 214 institutions and 166,680 cardiac catheterizations, is by far the largest study to evaluate this issue. It showed that both types of hemostasis devices may provide some protection against these complications. This study (Phase II) expands on the above study in the following ways: 1. It looks at some additional potential confounding variables that could provide an explanation for the apparent protective effects found in the first study. These additional variables include: activated clotting time (ACT) at the time of sheath removal; sheath size; current estrogen use; and history of previous interventional cardiac catheterization. 2. Individual assessment of the two different types of collagen plug devices (Angio-Seal™, St. Jude Medical, St. Paul, Minnesota, and VasoSeal®, Datascope Interventional Products, Mahwah, New Jersey). 3. Assessment of two additional devices, Chito-Seal™ (Abbott Vascular Devices, Redwood City, California) and the Syvek NT Patch® (Marine Polymer Technologies, Inc., Danvers, Massachusetts). These devices have been approved by the FDA as wound dressings, and not for vascular hemostasis. They are, however, sometimes used for hemostasis by physicians, generally in conjunction with some degree of manual or mechanical compression. 4. Assessment of local infection as one additional clinical outcome. Methods Source of data. The data used in this study were obtained from the American College of Cardiology-National Cardiovascular Data Registry™ (ACC-NCDR™).²³ In 1998 the ACC-NCDR began recruiting U.S. facilities with cardiac catheterization laboratories to join their registry program. This registry collects 142 core data elements needed for measuring the clinical management and outcomes of patients undergoing diagnostic cardiac catheterizations and percutaneous coronary interventions. They have recruited institutions for this registry program via general marketing methods, including mass mailings to all catheterization laboratory programs in the U.S., 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 June 2004, 498 institutions had joined the program. For this study, 59 sites were recruited to collect data from patients discharged between October 1 and December 31 of 2003. In conjunction with the normal data submission process, NCDR participants collected and submitted additional data designed specifically for this research project. Data quality. ACC-NCDR™ participants submit data quarterly. Prior to analyzing data submitted for any given quarter, Registry staff established the overall completeness of a participant’s data submission and provided feedback via a Data Quality Report (DQR) to the participant. 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. Ten specific complications and one aggregate category related to the femoral artery catheterization site were assessed: 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 > 3.0 gm/dl. Bleeding attributable to the vascular site could be retroperitoneal (retroperitoneal bleeding), a local hematoma > 10 cm. (hematoma bleeding), or external (entry site bleeding). Occlusion: Total obstruction of the artery by thrombus, usually at the site of access requiring surgical repair. Occlusions may be accompanied by the absence of a palpable pulse or Doppler. Loss of distal pulse: Loss of distal pulse requiring therapy. Dissection: A disruption of an arterial wall resulting in splitting and separation of the intimal (subintimal) layers. 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. AV fistula: A connection between the access artery and the accompanying vein demonstrated by arteriography or ultrasound and most often characterized by a continuous bruit. Infection: Infection occurring at the percutaneous entry site associated with a positive culture at the entry site and/or treatment with antibiotics. Surgical device removal: Necessity to surgically remove the closure device from the artery. Any vascular complication: Any of the above, other than infection Inclusion/exclusion criteria. Catheterization laboratory discharges for the last quarter of the year 2003 were included in the analysis. Excluded from the analysis were: 1) Any subject for whom information was not complete with regard to gender, type of procedure or type of hemostasis; 2) Admissions were excluded from the univariate analysis if they lacked information on the applicable variables, and from the individual multivariate analyses if they lacked information on any of the variables used in the final regression equation. Statistical analysis. We performed step-wise backwards multiple logistic regression using each of the outcome variables individually as the dependent variables, and using age, gender, race (white versus non-white), type of procedure (diagnostic versus interventional cardiac catheterization), type of hemostasis, body mass index (BMI), several indices of comorbidity (New York Heart Association classification, presence of diabetes, hypertension, peripheral vascular disease, left main coronary artery stenosis and shock, history of congestive heart failure, acute renal failure and previous recent interventional cardiac catheterization, emergency versus elective status of the procedure), sheath size and the number of cardiac catheterizations performed by the institution during the quarter (greater than or less than the average of 562). This analysis was performed separately for each outcome characterized by 25 or more occurrences. It was also performed separately for each device, and manual compression, characterized by 300 or more uses. The devices included Perclose (Abbott Vascular Devices), Vasoseal, Angio-Seal, Chito-Seal, Syvek Patch and mechanical compression. Device use was defined according to the first method of hemostasis used in each subject, regardless of what subsequent methods were used. For each multivariate analysis that assessed a specific device, the independent variable that indicated device use included only subjects for whom that device or manual compression was used as the first method of hemostasis. Thus, these analyses assessed the role of each device separately, using manual compression as a control. In each analysis, if the final regression equation did not include gender or device use, these variables were then added. Results Univariate analysis of adverse event rates by risk factor and device use. The sample size for this analysis was 13,878 (less for some outcomes because of missing values), including 4,179 manual compression controls. Vascular complications were reported in 3.37% of patients (Table 1), the most common being hematoma (2.0%), entry site bleeding (1.25%), and pseudoaneurysm (0.32%). Order of device use. More than one method of hemostasis was utilized in 32.8% of cases. When only one method of hemostasis was used, the overall rate of patients with adverse events was relatively low (2.92% for manual compression, 2.90% for mechanical compression and 1.14% when a specific device for hemostasis was used). When a second or third method of hemostasis had to be used, the rate was much higher (6.15% when manual compression was used first, 9.83% when mechanical compression was used first and 6.06% when a specific device for hemostasis was used first). Multivariate analyses. Table 2 indicates, for “any vascular complication”, the variables that were included in the final regression equation. Risks were significantly greater for females than for males (OR = 1.73; p 22 were not apparent in this study, we re-conducted the multivariate analysis leaving out the additional potential confounding variables that were added to this study, compared to the previous one. These included sheath size, hormone replacement therapy and history of interventional cardiac catheterization. This re-analysis had no substantive effect on the relationship between these hemostasis devices and the various outcomes. We also performed multivariate analysis separately for diagnostic and therapeutic cardiac catheterization (Table 4). This analysis showed that almost all of the positive association of VasoSeal with “any vascular complication” was attributable to diagnostic cardiac catheterizations (OR = 3.36; p Discussion of association of adverse outcomes with specific hemostasis devices and comparison with Phase I results. The most prominent new finding of the Phase II research was the relatively poor safety performance of VasoSeal — which could not be demonstrated in our Phase I study because the original ACC registry data did not differentiate between the two types of collagen plug devices. The reason why VasoSeal, of the two collagen plug devices, would present a greater risk of hemorrhagic adverse events is not known. It could be related to the fact that VasoSeal is placed on the outside of the artery over the puncture site in the tissue tract, whereas Angio-Seal makes use of both collagen in the tissue tract and an anchor, which is placed inside the artery — perhaps providing more tension and therefore a tighter fit. Whatever the specific cause, we believe that our findings are strongly suggestive that VasoSeal is, in most circumstances, less safe than either manual compression or the other most commonly used hemostasis devices due to the following reasons: • The high odds ratios for safety endpoints associated with VasoSeal (3.97 [2.04–7.71] with respect to entry site bleeding, 2.38 [1.47–3.85] with respect to “any vascular complication”; 3.36[1.85–6.12] with respect to “any vascular complication” for diagnostic procedures). • The fact that the association remains high after controlling for numerous potential confounding variables. • The apparent lack of an alternative plausible explanation. • The consistency of our epidemiological findings with the two meta-analyses of clinical trial results described above; this is of particular significance, since the weaknesses of epidemiological studies are counterbalanced by the strengths of clinical trials, and vice versa. The apparent protective effect of Perclose and the collagen plug devices seen in Phase I of this research was not confirmed in this study, but neither was it contradicted. This study showed no association with “any vascular complication” with either Perclose or the most commonly used collagen plug hemostasis device, Angio-Seal. However, in the case of Perclose, the point estimate was identical in both studies, thus the lack of statistical significance in this study could be attributable to its relatively lower sample size and power. In the case of Angio-Seal, there was a difference between the two studies (OR = 0.79 for combined collagen plug devices in Phase I; OR = 0.99 for Angio-Seal in phase II), and this difference would seem to hold more significance in that the odds ratio in the Phase I study was presumably raised by virtue of Angio-Seal being combined with VasoSeal. We can only speculate on the apparently relatively worse performance of Angio-Seal in this study as compared with the Phase I study: In our Phase I article²² we speculated that unmeasured, confounding variables might account for at least some of the apparent protective effects. In other words, physicians might be less likely to utilize these devices in situations where the local vascular situation gives them cause to worry about potential local adverse events. If that was the reason for some of the apparent protective effects shown in the Phase I study, it might be that, as more experience was gained with these devices over time, physicians became less likely to avoid using them in high risk situations, thus resulting in an amelioration of the apparent protective effects. Other substantive and new findings of our Phase II research, not discussed above, include the following: Perclose performs relatively worse (relative to manual compression controls and other hemostasis devices) with respect to entry site bleeding (OR = 1.57) than it does with respect to hematoma (OR = 0.49). An explanation for this could be that the tissue tract enlargement caused by the relatively large Perclose sheath (because of the relatively large diameter of the device) predisposes to bleeding at the entry site, whereas the device does a good job of sewing up the femoral artery, thereby preventing internal bleeding. Of the two patch devices, the Syvek Patch is much more strongly associated with entry site bleeding (OR = 1.54) than Chito-Seal (OR = 0.28). This may relate to the fact that Chito-Seal, unlike the Syvek Patch, is coated with a chitosan gel consisting of positively charged chitosan molecules that attract negatively charged red blood cells and platelets,³¹ leading to some degree of hemostasis at the entry site. The effectiveness of hemostasis for both devices, however, is undetermined since both are used in conjunction with some degree of manual or mechanical compression. Furthermore, the FDA has not approved either patch for use as a hemostasis device. The use of mechanical compression of the femoral artery is associated with a relatively low rate of entry site bleeding (OR = 0.65). An explanation for this may be that this procedure combines the advantages of hemostasis device use (i.e., a mechanism to stop bleeding that does not rely solely on manual compression, which may be applied more effectively by some users than by others) with the advantages of manual compression (i.e., the fact that the entry site is watched closely for a long period of time following sheath removal). The reason for the negative association between vascular complications and a history of recent interventional cardiac catheterization is not known. One possibility is that the recent procedure might have provided information that was of use for preventing vascular complications during the current procedure. Another new finding not evaluated in Phase I was that patients characterized by more than one type of hemostasis device were much more likely to experience local adverse events of all kinds. This is not surprising, given that many of these cases probably represent failure of the first used device. Limitations of findings due to limited follow-up. Although this study included outpatients, it is likely that many or most adverse events that occurred late, i.e., following discharge, were not reported and captured in this study. In an evaluation of recent reports to the FDA of adverse events associated with the use of hemostasis devices, between September 2003 and October 2004, 9 of 50 cases (18%) of bleeding and all 50 cases of infection occurred following discharge.¹ Pseudoaneurysms, in particular, are likely to be diagnosed late. Furthermore, the data with respect to pseudoaneurysms are somewhat problematic because institutions are likely to vary in the aggressiveness with which they look for complications such as this. All of this indicates the need for further research in this area. Literature review of the association between adverse outcomes and method of hemostasis. As noted in the introduction, various studies that have assessed complications following the use of hemostasis devices compared with manual compression have shown hemostasis devices to be safer, manual compression to be safer, or no difference. These differences have little to do with the type of hemostasis device studied, as these studies have shown a positive association between adverse events and the use of hemostasis devices when Angio-Seal,^15,16,18 VasoSeal,^14,18 and Perclose^15,17 have been used, as well as a negative association between all three of these devices²⁰ and adverse events. The widely differing results of these studies could be due to a number of factors, including their small size (and consequent lack of statistical power), the fact that most were performed at a single institution (which might have been characterized by varying skill levels), and the assessment of different outcomes. [For example, one study found a very high rate of a relatively minor adverse event (prolonged bleeding) in controls (13%) compared to device users (1.3%), but no difference in the rate of more serious adverse events,²⁴ and another study showed significantly more infectious complications with the use of Perclose, but significantly less hemorrhagic complications as compared with manual compression controls.²⁵] Two recent large meta-analyses assess the results of randomized controlled clinical trials of hemostasis devices^26,27 and overlap with each other to a substantial degree. Koreny et al. conclude their meta-analysis of 30 clinical trials which include a total of about 4,000 patients by saying that when analysis was limited to trials that used intention-to-treat analysis, hemostasis devices were associated with a higher risk of hematoma and pseudoaneurysm.²⁶ Although they note that their analysis was not influenced by the type of device, using the data from their tables shows that VasoSeal performed substantially worse against controls than either Perclose or Angio-Seal with respect to the three most frequently reported outcomes — hematoma, bleeding, and pseudoaneurysm: VasoSeal was characterized by an 18.5% rate of hematoma, compared to 14.0% for controls (p = 0.05); 3.4% versus 2.0% for bleeding (p = 0.19) and 4.9% versus 2.9% for pseudoaneurysm (p = 0.06); Angio-Seal and Perclose, on the other hand, performed slightly better than controls with respect to these outcomes. The meta-analysis performed by Vaitkus²⁷ looked at 16 clinical trials which included 5,048 patients and concluded that, although when the analysis of several safety outcomes included all types of hemostasis devices together, the devices performed better than controls (OR = 0.89), when looked at separately, Angio-Seal performed better than controls (OR = 0.51), VasoSeal performed worse than controls (OR = 1.18), and Perclose performed the same as controls (although Perclose performed better than controls following diagnostic cardiac catheterization.) The results of these meta-analyses must be interpreted with caution. First, even the one that contained the larger number of patients included only 5,048, and the one that contained the larger number institutions included only slightly more than 30 institutions. Furthermore, the results of the various studies varied greatly. For example, although Vaitkus’ analysis demonstrated significantly more adverse events in patients receiving VasoSeal than in controls, this analysis included only 8 studies, two of which demonstrated significantly less adverse events in VasoSeal users than in controls,^24,28 2 that demonstrated about the same rate for VasoSeal as for controls,^4,29 and 4 that demonstrated a nonstatistically significant higher rate in VasoSeal users than in controls.>^5,10,14,30 One may conclude from all of this that the performance of these devices is greatly dependent upon the institution in which they are used and the skill of the individual users. This conclusion is further supported by the fact that this study showed a significant inverse association between the number of cardiac catheterizations performed at an institution and the rate of adverse events. Conclusion Our finding of relatively high rates of local vascular complications associated with VasoSeal use, compared with both other hemostasis devices and manual compression controls, particularly following diagnostic cardiac catheterization, is information that practitioners should consider when deciding what hemostasis device to use. The fact that these findings are consistent with medical literature reviews of clinical trials supports this recommendation.

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