Efficacy of a Novel Procedure Sheath and Closure Device during
Diagnostic Catheterization: The Multicenter Randomized Clinical

Multiple devices are currently available for closure of the femoral artery access site after cardiac catheterization.¹ Currently, the most widely used closure devices are the Angio-Seal^™ device (St. Jude Medical, St. Paul, Minnesota)^2–4 and the Perclose^®2,5 and StarClose^™,² devices (Abbott Vascular, Redwood City, California). The aim of these devices when compared to manual compression is to safely improve patient comfort, decrease time to hemostasis with earlier ambulation and expedited hospital discharge, thereby ultimately improving catheterization laboratory throughput. There is evidence that these devices may also reduce vascular complications compared to manual hemostasis.^6,7 Currently, no closure device is considered superior and universally utilized in achieving hemostasis compared to other closure devices or manual pressure.² The Femoral Introducer Sheath and Hemostasis, or FISH^™ device (FISH, MIR Corp., Bloomington, Indiana), is unique in that an extracellular matrix closure patch is premounted onto a 5, 6 or 8 Fr access sheath. This combines access and closure on the same device, with the potential for simplification of these two steps. The extracellular matrix patch may be important for tissue repair and remodeling.⁸ The objective of this project was to report the efficacy and safety of the FISH device compared to manual pressure among United States catheterization laboratories.

Methods
The FISH pivotal investigation was a multicentered, prospective, randomized, controlled trial conducted at 8 catheterization laboratories in the United States. This trial was designed to study two patient populations: a diagnostic cohort and an interventional cohort. Enrollment for the completed diagnostic portion of the study was from January 2004 to July 2006. Efficacy outcomes were reported from this diagnostic cohort. Enrollment for the interventional cohort is partially completed and will be reported fully at a later date. Since adverse events were relatively infrequent, the interventional patients enrolled to date were combined with the diagnostic patients to comprise the safety data of the trial.
Patients who were between the ages of 18 and 80 years, agreed to return for 30-day follow up, provided written informed consent and were candidates for diagnostic or interventional coronary angiography were eligible for enrollment. Comprehensive exclusion criteria are listed in the appendix.
The original study design allowed for patient withdrawal after randomization and sheath placement if suboptimal hemostasis was anticipated. Potential reasons for anticipated suboptimal hemostasis included placement of the sheath at or below the bifurcation of the femoral artery, intraprocedural bleeding or hematoma around the sheath, difficulty attaining arterial access that required multiple punctures, and difficulty with sheath insertion due to scarring or tortuosity. Efficacy outcomes were not recorded among the early-withdrawal patients, nor were they considered device failures per se.

The FISH device was placed in the following manner: arterial access was obtained with a hollow-bore needle with 1 cm markings and the guidewire was inserted into the common femoral artery. The needle depth was noted prior to removal to serve as a gauge to position the FISH device. As clinically indicated, predilatation of the arteriotomy was performed. The FISH device was then inserted to the premeasured depth, and a release wire was pulled, which allowed the bioabsorbable extracellular matrix “patch” to become independent of the sheath. The patch is made from porcine small intestinal submucosa (SIS) and retains the original composition of collagen, glycosaminoglycans, proteoglycans and glycoproteins. At the conclusion of the procedure, a compression suture is pulled, which firmly incorporates the patch around the arteriotomy (Figures 1 and 2). The SIS patch is resorbed in 90 days.
Patients were randomly assigned on a 2:1 basis to the FISH device versus manual compression. Diagnostic participants did not receive anticoagulation, while interventional participants were anticoagulated according to physician preference or hospital standard. Prior to randomization, there was a roll-in training period where each investigator had the opportunity to perform 2 cases using the FISH device.
Efficacy was determined during the index hospitalization, with follow up extended to 30 days to assess device safety. Approximately half of the patients underwent ultrasonographic evaluation of the common femoral artery at the 30- day follow-up visit. Primary efficacy endpoints included time to hemostasis and time to ambulation. Time to hemostasis was defined as absence of oozing blood that was readily treated by light compression methods (i.e., pressure dressing and additional manual pressure). Time to ambulation was defined as time from sheath removal until the time when the patient stood at the bedside and walked at least 20 feet without rebleeding. Secondary efficacy endpoints included time to eligible discharge and time to actual discharge. Time to eligible discharge was defined as the time the patient ambulated, and the femoral access site was determined to be stable, including distal pulses and neurovascular status of the extremity. Severe adverse safety events included bleeding that required transfusion, access-site-related infection, access-site-related vascular injury that required surgical or percutaneous repair and permanent nerve injury. Minor adverse safety events included a hematoma larger than 6 cm, pseudoaneurysm and an arteriovenous fistula. Device or compression failure was defined as failure to achieve hemostasis within 60 minutes, with the need for external mechanical compression to control bleeding.
Sample size was calculated for a noninferiority trial design based on an expected major adverse event rate of 4% for the control group and a maximum allowable event rate of 9% for the FISH group. For 80% power at 5% significance level, 407 patients would be required. Categorical variables were compared by Fisher’s exact test, and comparison of means was performed by the Wilcoxon two-sample test. All p-values are two-sided, with statistical significance considered at a p-value < 0.05.

Results
Initially, 354 patients were screened for the study. Twenty- nine randomized patients were withdrawn early, with 27 in the FISH device arm (4 of these were also roll-in patients), and 2 in the manual compression arm. Indications for early patient withdrawal included common femoral artery scarring or tortuosity (n = 10), difficult arterial access with multiple punctures (n = 6), periprocedural access-site bleeding (n = 6), placement of ipsilateral venous sheath (n = 3) and miscellaneous other reasons (n = 4). An additional 28 participants were roll-in patients, which resulted in 297 randomized patients; 191 patients were randomized to the FISH device (139 diagnostic and 52 interventional), and 106 patients to the control group (67 diagnostic and 39 interventional). Ultrasonographic evaluation was performed in one-half of the patients. The baseline characteristics of the study participants are found in Table 1. Eleven patients were lost to follow up.

For the diagnostic cohort only, the mean time to hemostasis was 8.9 minutes (median = 6, standard deviation [SD] = 6.7, minimum-maximum = 2–40) for the FISH device, compared to 17.2 minutes (median = 17, SD = 6.7, minimum-maximum = 7–55) for manual compression (p < 0.0001) (Figure 3).
The mean time to hemostasis was 8.1 minutes for women, compared to 9.4 minutes for men (p = 0.29). The mean time to ambulation was 2.4 hours (median = 2.0, SD = 2.1, minimum-maximum = 0.9–19.6) for the FISH device, compared to 4.3 hours (median = 4.2, SD = 1.0, minimum-maximum = 1.3–7.3) for manual compression (p < 0.0001). The mean time to eligible discharge was 3.0 hours for the FISH device, compared to 5.5 hours for manual compression (p < 0.0001). The mean time to actual discharge was 16.2 hours for the FISH device, compared to 24.9 hours for manual compression (p < 0.0001). The mean time to discharge was 5.2 hours for women, compared to 20.9 hours for men (p = 0.029).
For the entire cohort (diagnostic and interventional patients), there were 4 device failures and no manual compression failures (p = 1.0). One death occurred in the FISH group several days after the index procedure. No deaths occurred in the manual compression group (p = 1.0). One episode of access-site-related bleeding that required transfusion occurred in the FISH group, compared to no transfusions in the manual compression group (p = 1.0). No other serious adverse safety events were seen in either study group. In the FISH group, 3 access-site hematomas and 2 pseudoaneurysms treated wit thrombin injection were documented, compared with 2 access site hematomas and 1 pseudoaneurysm in the manual compression group (p = 1.0).

Discussion
The results of this multicentered, randomized clinical trial demonstrate superiority of the FISH device in achieving hemostasis and time to ambulation compared to manual compression among diagnostic participants. The time to eligible discharge and time to actual discharge were also superior with the FISH device compared to manual compression. Men and women had similar times to hemostasis, although the time to actual discharge was shorter among women.
There was no apparent difference in the need for transfusion, the incidence hematoma or pseudoaneurysm between the FISH device and manual compression among diagnostic and interventional participants. There were no infections, nerve injury or other serious adverse events in either group. The only death occurred in a patient who had received a FISH device, although this was felt to be non-device-related. This death occurred in a patient with multiple comorbidities, including hypertrophic cardiomyopathy and reduced left ventricular systolic function who underwent a diagnostic catheterization and immediately developed a large hematoma upon sheath removal. The following day, the patient experienced sudden pain at the access site, and was diagnosed with a pseudoaneurysm which was treated with thrombin injection and blood transfusion. Over the next 3 days, the patient’s hemoglobin and hematocrit remained stable, although he experienced an arrest of unclear etiology that ultimately led to his death. It is well known that hematomas and pseudoaneurysms can develop with vascular closure devices as well as with manual compression.⁹
There were 4 FISH device failures (incidence = 2.1%). Ongoing research will need to determine if this failure rate remains true outside of a randomized trial setting as well as in exclusively anticoagulated patients. Failure rates of 2.9% and 5.9% in anticoagulated patients have been observed with the Angio-Seal and Perclose devices, respectively.⁷ In the current trial there was no obvious difference between serious or minor adverse events, although a limitation of the study is that it was underpowered to detect a difference in such infrequent events. Ongoing research and clinical surveillance will be required to more precisely determine the true incidence of adverse events with the use of this device. The shorter time to hospital discharge in women compared to men was likely due to chance, since there were 4 male outliers with relatively long time to discharge due to reasons that were unrelated to the use of the closure device. Additionally, there was no significant difference in time to hemostasis based on gender.
While vascular closure devices are convenient to both the patient and the catheterization laboratory, their routine use in preventing vascular complications has been controversial.^9–11 There is now increasing evidence that the use of closure devices is associated with a reduction in vascular complications.^6,7,12,13 One recent study examined over 12,000 patients in a high-volume catheterization laboratory that routinely used vascular closure devices and documented a 0.7% incidence of complications among diagnostic patients and a 2.7% incidence among interventional patients.6 The use of vascular closure devices, after adjustment by propensity analysis, was associated with a 58% reduction in complications among diagnostic patients and a 42% reduction among interventional patients. Another study meta-analyzed over 37,000 registry and randomized trial patients and documented a trend towards a reduction in vascular complications in an interventional setting with the use of the Angio-Seal device.¹² A separate analysis similarly found a trend towards a reduction in vascular complications with Angio-Seal, but not with the Perclose, compared to manual compression.¹³
Study limitations. Several limitations need to be mentioned. The first limitation was the significant number of early withdrawals in the FISH arm. Although the original trial design allowed for early withdrawals to occur if suboptimal hemostasis was anticipated with the use of a closure device, this produced a bias against manual compression since only 2 patients in the control arm were withdrawn early. The intention-to-treat principle was not possible, since time to hemostasis was not collected in patients who crossed over to manual compression. Despite this, the conditions that led to early withdrawals can be considered a failure of devices in general, which needs to be carefully considered when deciding on the preferred strategy for hemostasis. The second limitation is that safety data were available for the entire cohort, although efficacy data were only available for the diagnostic cohort. If hemostasis times from the partially-completed interventional cohort had been included with the diagnostic cohort, this would have likely negatively impacted the time to hemostasis and time to ambulation with the FISH device. Despite including the entire study population for safety outcomes, there was still a lack of power to detect a difference in adverse events between the two groups. The next limitation is that the FISH SIS patch straddles the arteriotomy so that a portion of it resides intravascularly as well as extra-vascularly. Although the device is nonthrombogenic, this feature needs to be considered within the context of new devices (e.g., StarClose) where only extravascular closure takes place. The fourth limitation is that since there were only 2 roll-in cases per investigator, it is likely that the operators were still in the learning process of optimal device use while data were being collected, thus producing a bias against the FISH device.¹⁴ Moreover, with numerous study investigators, the number of devices deployed per investigator was relatively low. Lastly, only half of the study participants underwent ultrasonographic examination which may have underestimated the number of vascular complications detected in the study.

Conclusion
In summary, the FISH device is a novel access sheath and closure device combined on the same system with the intent to simplify access and vascular closure. This multicentered trial involving nearly 300 patients documented significantly reduced time to hemostasis, time to ambulation, and time to discharge with the use of the FISH device compared to manual compression in patients without anticoagulation. A significant proportion of patients who received the FISH device were converted to manual compression due to anticipated suboptimal hemostasis. For select patients, the use of the FISH device may be considered an alternative means to achieve access and hemostasis. Ongoing research is needed to determine the safety and efficacy of this device compared with currentlyavailable vascular closure devices, especially among anticoagulated patients.

Appendix
Study exclusion criteria: Known significant bleeding or platelet disorder, Von Willibrand’s disease, anemia (hemoglobin < 10 gm/dL, hematocrit < 30 %), thrombasthenia, systemic hypertension (> 180 mmHg systolic) unresponsive to treatment, pregnant or lactating patient, activated clotting time > 400 seconds, a known allergic reaction to pork products or any other material used in the device, preexisting immune deficiency, need for a sheath size > 8 Fr, arterial closure site depth > 7.5 cm, ipsilateral arterial site closure with manual compression £ 6 weeks before the procedure.

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