Abstract: Objectives. To evaluate the safety and accuracy of the Early Bird Bleed Monitoring System (EBBMS; Saranas) for the detection of access-site related bleeds in humans undergoing endovascular procedures. Background. Bleeding complications after endovascular procedures are frequent and associated with poor prognosis. The EBBMS is a novel technology designed to detect in real time the onset, progression, and severity of internal bleeds. Methods. The EBBMS was used during and after endovascular procedures, either as a venous or arterial access sheath. The primary endpoint was the level of agreement in bleed detection between the Saranas EBBMS and postprocedural computed tomography. Results. From August 2018 to December 2018, a total of 60 patients from five United States sites were enrolled and underwent elective endovascular procedures (transcatheter aortic valve replacement [67%], percutaneous coronary intervention [13%], percutaneous ventricular assist device [8%], balloon aortic valvuloplasty [7%], transcatheter mitral valve repair/replacement [4%], and endovascular aneurysmal repair [2%]). The EBBMS detected the absence of bleeds in 21 patients (35%) and bleeds in 39 patients (65%), with bleeding severity level 1 in 20 patients (33%), level 2 in 15 patients (25%), and level 3 in 4 patients (7%). Bleeding detection occurred during the procedure in 31% of patients and post procedure in 69% of patients. The level of agreement between the EBBMS and computed tomography scan was high (Cohen’s kappa=0.84). No device-related complications were reported. Conclusions. The EBBMS was safe across a variety of endovascular procedures and detected bleeding events with a high level of agreement with postprocedural computed tomography scan.
J INVASIVE CARDIOL 2020;32(7):255-261. Epub 2020 June 8.
Key words: bleeding complications, Early Bird Bleed Monitoring System, new device
Periprocedural bleeding events in patients undergoing endovascular procedures are frequent and associated with increase morbidity, mortality, and cost.1-3 Recently, there has been a marked increase in large-bore catheter procedures, such as transcatheter aortic valve replacement (TAVR), percutaneous ventricular assist device (PVAD), and endovascular aneurysm repair (EVAR), as well as complex and high-risk percutaneous coronary intervention (PCI). Patients undergoing these endovascular procedures tend to be at elevated bleeding risk due to their comorbidities and clinical characteristics, and major bleeding events are expected to remain a major risk of these procedures.3-5
Early detection of access-related bleeding complications remains challenging, as clinical recognition mainly relies on the occurrence of signs and symptoms (hematoma, pain, hypotension, and sometimes death)6 and additional imaging confirmation (ultrasound, computed tomography [CT]).7 By the time these bleeds become symptomatic or are confirmed by imaging, substantial blood loss has usually already occurred and patient prognosis may have been compromised. If bleeding events are detected early, subsequent prompt management could potentially mitigate the detrimental effect of such bleeds. Currently, no technology is available that can detect and alert clinicians of an ongoing internal bleeding complication in real time. The Early Bird Bleed Monitoring System (EBBMS; Saranas) is a novel technology that has been designed to detect the onset and progression of an internal bleed and to provide early notification to clinicians (Figure 1). Prior work has demonstrated the performance of the EBBMS (sensitivity and specificity of 100%) in detecting the onset of access-related bleeds in an animal model, and its capacity to track the progression and quantify the severity of bleeding.8 The present first-in-human study reports on the safety and accuracy of the Saranas EBBMS for the detection of access-site related bleeding events during and after endovascular procedures.
Study population. Patients undergoing elective percutaneous endovascular procedures via femoral arterial or venous access were prospectively enrolled. Key exclusion criteria were: (1) inability to access the common femoral artery or vein; (2) unstable conditions, such as cardiogenic shock or ST-elevated myocardial infarction; (3) current active bleeding; and (4) preprocedural conditions precluding the realization of a postprocedural CT scan. Patients provided written informed consent before enrollment. After an informed consent process, subjects underwent screening procedures and were scheduled for their endovascular procedure. A CT scan with or without contrast was recommended prior to the endovascular access procedure to assess for the presence of prior recent bleeding events or vascular complications.
Study device. The Saranas EBBMS includes a standard introducer sheath with a real-time bleed detection system designed to continuously sense and measure changes in local bioimpedance (Figure 1). The EBBMS consists of the following: (1) a standard vascular access sheath (6 Fr or 8 Fr) with standard sheath function (intravascular part, in vein or artery; Figure 1A); (2) 4 electrodes (2 proximal, 2 distal) embedded within the sheath; and (3) a user interface display (integrated on the side port of the sheath; Figure 1B). The user interface display houses a printed circuit board assembly that runs a proprietary algorithm that analyzes bioimpedance and can trigger visible and audible indicators to communicate changes in bioimpedance (indicative of extravascular blood accumulation) (Figure 1C). The display features a 3-level bleed indicator system that sequentially illuminates light-emitting diode (LED) indicators to show an increase in bleed progression to 3 levels. The level 1 indicator (first LED) is triggered by the early onset of a bleed (~50 mL of bleed) and is accompanied by momentary activation of an audible tone. The level 2 indicator (second LED) is triggered as the bleed progresses to a predetermined bioimpedance threshold (~100 mL of bleed) and is accompanied by a longer-duration audible tone. The level 3 indicator (third LED) is triggered as the bleed continues to progress further ~200 mL of bleed) to a higher bioimpedance threshold (Figures 1C and 1D). The audible tone activated at this level is continuous and requires the clinician to silence the device by pressing a button on the display.
Study design. The Early Bird first-in-human study was a prospective, multicenter, single-arm first-in-human clinical study of subjects undergoing an elective endovascular procedure (Figure 2). The study was approved by the institutional review board at each participating site, and all patients provided written informed consent. A data and safety monitoring board had access to all study data. All serious adverse events were site reported. All data were analyzed by independent consulting biostatisticians. The endovascular procedure was performed per each institution’s standard practice, with monitoring using the Saranas EBBMS in either the femoral vein or artery. Following completion of the procedure, subjects were monitored for internal bleeding using the Saranas EBBMS for up to 12 hours, and a CT scan (without contrast, unless otherwise indicated) was performed to confirm or identify any bleeding events. After this period of time, the EBBMS was removed and sent back to Saranas for analysis. An independent core laboratory (Medical Metrics) assessed all CT scans. Adverse events and device effects were recorded from enrollment of subjects and throughout the procedure and hospitalization until discharge. The study was registered at www.ClinicalTrials.gov (NCT03621202) as Safety and Accuracy of the Saranas EBBMS for the Detection of Endovascular Procedure Related Bleeding Events.
Study endpoints. The primary endpoint of the study was the level of agreement in bleeding detection between the Saranas EBBMS and postprocedural CT, defined as the concordance of any bleeding as assessed by the independent CT core laboratory and any bleeding notification (level 1, 2, or 3) as detected by the Saranas EBBMS. Other important secondary endpoints included in-hospital mortality, stroke, Valve Academic Research Consortium (VARC)-2 major vascular complications, and VARC-2 major or life-threatening bleeding.9
Statistical analysis. Continuous outcome variables are presented as mean ± standard deviation and as median (interquartile range [IQR]). For categorical outcome variables, relative frequencies were provided. Level of agreement in bleeding detection between the Saranas EBBMS and postprocedural CT was assessed by Cohen’s kappa.10 Statistical analyses were performed using SAS, version 9.2 (SAS Institute).
Patients and enrollment. From August 2018 to December 2018, a total of 66 patients were enrolled from five United States centers. Six of these patients were excluded for lack of available postprocedural CT scan data, leading to a total of 60 patients representing the final population for analysis. The baseline and procedural characteristics of the patients are presented in Table 1. The mean age was 76 ± 10 years and 25 patients (42%) were female. The index procedure was TAVR in 40 patients (67%), PCI in 8 patients (13%), PVAD insertion and removal in 5 patients (8%), balloon aortic valvuloplasty in 4 patients (7%), edge-to-edge mitral valve repair with MitraClip in 1 patient (2%), transcatheter mitral valve replacement (TMVR) in 1 patient (2%), and EVAR in 1 patient (2%).
Procedural characteristics. Table 2 summarizes details regarding the different vascular accesses performed. Among the 60 index procedures, 58 (97%) were performed from the femoral artery and 2 (3%) were performed from the femoral vein (edge-to-edge mitral valve repair with MitraClip and TMVR). The vast majority of the procedures (85%) involved large-bore catheter insertion (>10 Fr diameter). Concomitantly, the EBBMS (6 Fr, 53%; 8 Fr, 47%) was inserted in a femoral vein in all procedures. For the index procedures performed via the femoral artery, the EBBMS was inserted in the ipsilateral vein to monitor bleeding occurrence. For the 2 index procedures performed via the femoral vein, the EBBMS was inserted in the same vein, but at an insertion site slightly distal to the main large-bore access. Vascular hemostasis was achieved in the majority of cases (82%) with a double-Perclose ProGlide (Abbott Cardiovascular) technique. A crossover occlusion-balloon technique was used prophylactically in 9 patients (15%) and in a reactive fashion for suboptimal hemostasis in 9 patients (15%). Mean procedure time (from first needle stick to final hemostasis achieved, excluding the EBBMS) was 103 ± 73 minutes, and mean bleeding monitoring time by the EBBMS (from insertion/activation to removal) was 262 ± 99 minutes.
Periprocedural bleeding as detected by the EBBMS. Table 3 and Figure 3A show the rates of periprocedural bleeding as detected by the EBBMS related to the index procedure. No bleeding was detected in 21 patients (35%), while bleeds were detected in 39 patients (65%). Among patients with a bleed identified by the EBBMS, level 1 bleed severity was detected in 20 patients (33%), level 2 bleed severity was detected in 15 patients (25%), and level 3 bleed severity was detected in 4 patients (7%). The timing of bleed detection is also shown among the 39 patients with bleeds identified by EBBMS in Table 3 and Figure 3B. Twelve patients (31%) had a bleed detected during the procedure and 27 patients (69%) had a bleed detected during the postprocedural period. The mean time of bleed detection was 80 ± 95 minutes for a level 1 bleed, 110 ± 68 minutes for a level 2 bleed, and 143 ± 53 minutes for a level 3 bleed.
Level of agreement between the EBBMS and postprocedure CT. Independent core laboratory analysis of the 60 postprocedural CT scans of the abdomen and pelvis area demonstrated 4 patients (7%) with normal findings, 34 patients (57%) with some level of subcutaneous tissue infiltration, and 22 patients (37%) with hematoma at the index procedure access site. No retroperitoneal bleeds were detected. The level of agreement between CT scan findings and the EBBMS, as determined by Cohen’s kappa statistic, was 0.84, signifying a high level of agreement for detection of any bleeding. The EBBMS sensitivity was 100%, specificity was 75%, positive predictive value was 98%, and negative predictive value was 100% for bleed detection relative to CT scan findings.
Clinical outcomes. During the index hospitalization, 2 patients (3%) died (1 from non-access related death due to stroke [TMVR valve in mitral annular calcium] and 1 from urosepsis post TAVR). Clinical bleeding events occurred in 7 patients (12%); 3 (5%) were non-access related (2 patients underwent transfusions for chronic anemia and 1 patient had a pericardial effusion) and 4 (7%) were access related. Among those 4 patients experiencing access-related bleeding, 1 patient (2%) had a major bleed and 3 patients (5%) had minor bleeding. All 4 patients had appropriate detection of the bleed by the EBBMS and confirmation by CT scan. One patient (2%) had a major vascular complication that occurred related to a failed closure device and 1 patient (2%) had a minor vascular complication (pseudoaneurysm) with no clinical sequelae.
The current report, drawn from 60 patients undergoing a variety of elective endovascular procedures, demonstrates for the first time in humans the safety and accuracy of the EBBMS for the real-time detection and monitoring of access-site related bleeding events. The principal findings of the EBBMS first-in-human study are as follows: (1) the EBBMS demonstrates a high level of agreement with postprocedural CT scan to identify periprocedural bleeding events; (2) the EBBMS identifies the absence of significant bleeding in 35% of patients and the presence of potential bleeds in 65% of patients; and (3) among patients with EBBMS reported bleeding, approximately one-third occurred during the procedure and approximately two-thirds occurred after the procedure.
Bleeding events after endovascular procedures are frequent and associated with increased mortality, morbidity, length of stay, and cost.1 The detrimental impact of bleeding events has been demonstrated for both large-bore1 and small-bore vascular access.2 While bleeding-avoidance strategies11,12 and technique optimization for vascular access (ultrasound guidance, micropuncture technique)13,14 and vascular hemostasis15 have been shown to improve outcomes, bleeding complications still occur. Indeed, recent data related to contemporary and emerging large-bore endovascular devices demonstrated a high rate of bleeding complications,5 preventing patients from fully benefiting from these procedures.
The EBBMS is a novel technology designed to detect bleeding early and monitor its progression. A recent animal study demonstrated the capacity of the EBBMS to detect access-related bleeding as low as ~50 mL (level 1) and to continuously assess its progression (level 2, ~100 mL; level 3, ~200 mL).8 The concept of early bleeding detection, during its presymptomatic stage, allows the clinician to take preemptive action to impede the progression of bleeding and potentially mitigate its deleterious consequences. Similar to the animal study, the current study demonstrated high sensitivity and specificity for bleed detection, with a strong level of agreement with postprocedural CT scan. These data are important and support the capacity and accuracy of the EBBMS to detect bleeding complication in humans.
One important finding of the current study is that approximately one-third of the bleeds occurred during the index procedure and more than two-thirds occurred in the postprocedural phase while outside the procedure room. This finding is important since the level of bleed surveillance in the recovery phase is known to be less than during the procedure itself. Our study finds a mean procedure time of ~100 minutes, with a mean time of 80 minutes for level 1 bleed notification, 110 minutes for level 2 bleed notification, and 140 minutes for level 3 bleed notification. Those findings illustrate that periprocedural bleeding may have begun during the procedure, and while mild in severity at that time (level 1), might progress to a more clinically significant level (level 2 or level 3) during the recovery phase, approximately 2-3 hours after the procedure. Those findings are in line with contemporary clinical experience, in which severe bleeds often occur within the first 4 hours post procedure. This highlights the utility of the EBBMS device in the early postrecovery phase of endovascular procedures, at least among patients at high risk for bleeding (eg, those with obesity, frailty, severe peripheral artery disease, steroid use) or high-risk procedures (eg, large-bore catheter use, thrombolytic or additional antithrombotic agents used, shock state, suboptimal access or closure).
Conversely, 35% of patients did not have any bleeding detected by the EBBMS. This finding is also important and identifies a subgroup of patients who could potentially benefit from a more optimal recovery and discharge pathway with decreased hospital resource use. Postprocedural surveillance in the intensive care unit is costly and not always necessary,16 and EBBMS individualization of patient disposition, such as intensive care unit avoidance or same-day discharge in selected cases,17 might become an attractive strategy, especially in a time when bed resources and capacity for a lengthy hospital stay are limited.18,19
Study limitations. The current report describes the first-in-human case series of the use of the EBBMS during endovascular procedures. The sample size was small, the study had a single arm with no comparator, and the impact of the use of EBBMS on clinical outcomes or cost effectiveness remains unknown. Whether the ability to detect bleeding before progression to a more severe or symptomatic phase will improve clinical outcomes and improve hospital resource utilization will be addressed in a larger upcoming clinical study. A low complication rate (bleeding, vascular complications) was observed in the current study. This could be due to multiple factors such as the low number of patients (play of chance), the elective nature of the study procedures, the high experience/volume of the enrolling sites, and potentially the use of the EBBMS. Finally, the current EBBMS categorizes bleeding into four categories. The next device iteration will allow for enhanced monitoring with continuous display of the bioimpedance signal itself, allowing for more flexibility in data interpretation and clinical response.
Among an all-comer population of patients undergoing a broad variety of endovascular procedures, the EBBMS was safe and accurate for the early detection of access-site related bleeding events.
From the 1Gagnon Cardiovascular Institute, Morristown Medical Center, Morristown, New Jersey; 2NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York; 3Texas Heart Institute, Houston, Texas; 4Vanderbilt Health Nashville, Nashville, Tennessee, 5North Florida Regional Medical Center, Gainesville, Florida; 6Saranas, Inc., Houston, Texas; 7Duke University School of Medicine, Durham, North Carolina; 8Ascension St. John Hospital, Detroit, Michigan; 9Clinical Trials Center, Cardiovascular Research Foundation, New York, New York; and 10The Vascular Experts, Old Saybrook, Connecticut.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Généreux reports speaker fees from Edwards Lifesciences, Cordis, Medtronic; consultant fees from Abiomed, Boston Scientific, Cardiovascular Systems, Inc, Cordis, Edwards Lifesciences, Medtronic, Opsens, Soundbite Medical Solutions, Pi-Cardia, Saranas, Siemens, SIG.NUM; shareholder in Soundbite Medical Solutions, SIG.NUM, Pi-Cardia, Puzzle Medical. Dr Nazif reports consultant fees from Edwards Lifesciences, Boston Scientific, Medtronic; equity in Venus Medtech. Dr Klodell reports grant support from Edwards Lifesciences, Medtronic, Boston Scientific; speaker/consultant/proctor/training site income from Edwards Lifesciences, Medtronic, Abbott Vascular. Dr Patel reports grant support from Bayer, Janssen, Heartflow, NHLBI; advisory board/consultant income from Bayer, Janssen, Heartflow, Saranas. Dr Kaki reports advisory board income from Abiomed, Cardiovascular Solutions, Abbott Vascular, Saranas; proctor income from Abiomed. Dr Kirtane reports institutional funding to Columbia University and/or the Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, Cardiovascular Solutions, CathWorks, Siemens, Philips, ReCor Medical; in addition to research grants, institutional funding includes fees paid to Columbia University and/or the Cardiovascular Research Foundation for speaking engagements and/or consulting (no speaking/consulting fees were personally received); personal travel expenses/meals from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, Cardiovascular Solutions, CathWorks, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron. Mr Syed and Mr Bueche are employees of Saranas. Dr Razavi is a founder of Saranas. Dr Karmpaliotis reports consulting fees from Abbott Vascular, Boston Scientific, and Abiomed; equity from Saranas, Soundbite Medical Solutions, and Traverse Vascular. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript submitted May 14, 2020, provisional acceptance given May 18, 2020, final version accepted May 19, 2020.
Address for correspondence: Philippe Généreux, MD, Gagnon Cardiovascular Institute, Morristown Medical Center, 100 Madison Avenue, Morristown, NJ 07960. Email: email@example.com
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