Prospective Multicenter Randomized Controlled Trial (PDF)

DOI: 10.1111/jocs.14376 ORIGINAL ARTICLE Prospective, multicenter, randomized, controlled trial evaluating the performance of a novel combination powder vs hemostatic matrix in cardiothoracic operations Nicholas C. Dang MD1 | Abbas Ardehali MD2 | Brian A. Bruckner MD3 | Patrick E. Parrino MD4 |...

DOI: 10.1111/jocs.14376 ORIGINAL ARTICLE Prospective, multicenter, randomized, controlled trial evaluating the performance of a novel combination powder vs hemostatic matrix in cardiothoracic operations Nicholas C. Dang MD1 | Abbas Ardehali MD2 | Brian A. Bruckner MD3 | Patrick E. Parrino MD4 | Daniel L. Gillen PhD5 | Rachel W. Hoffman BSE6 | Russell Spotnitz MD6 | Stephanie Cavoores BSN6 | Ian J. Shorn BSE6 | Roberto J. Manson MD6,7,8 | William D. Spotnitz MD, MBA6,9 1 Department of Surgery, Kaiser Moanalua Medical Center, Honolulu, Hawaii Abstract 2 Department of Surgery, University of Aim: This trial compared the hemostatic performance of a novel combination powder California at Los Angeles, Los Angeles, (CP) to a control hemostatic matrix (HM) in cardiothoracic operations. California 3 Methodist DeBakey Heart and Vascular Methods: Patients meeting eligibility criteria were enrolled after providing informed Center, Houston Methodist Hospital, Houston, consent. Subjects were randomized intraoperatively to receive CP (HEMOBLAST Texas 4 Bellows; Biom’up, France) or HM (FLOSEAL Hemostatic Matrix; Baxter Healthcare Thoracic and Cardiovascular Surgery Section, Ochsner Medical Center, New Orleans, Corporation, Hayward, CA). Bleeding was assessed using a clinically validated, Louisiana quantitative bleeding severity scale. The primary endpoint was total time to 5 Department of Statistics, University of California, Irvine, California hemostasis (TTTH), from the start of device preparation, as an indicator of when a 6 Biom'up SA, Lyon, France surgeon asks for a surgical hemostat until hemostasis was achieved. TTTH at 7 Department of Surgery, Duke University, 3 minutes was utilized for the primary analysis, while TTTH at 5 minutes was Durham, North Carolina considered as a secondary endpoint. 8 Department of Mechanical Engineering and Materials Science, Duke University, Durham, Results: A total of 105 subjects were enrolled across four institutions. The primary North Carolina efficacy endpoint for the superiority of CP relative to HM for success at achieving 9 Department of Surgery, University of hemostasis within 3 minutes was met, with 64.2% of the CP group achieving Virginia, Charlottesville, Virginia hemostasis compared with 9.6% of the HM group, a difference of 54.54% (37.4%‐ Correspondence 71.6%; P <.001 for superiority). The secondary efficacy endpoint was also met, with William D. Spotnitz, MD, 2738 SW 92nd Drive, Gainesville, FL 32608. 92.5% of the CP group achieving hemostasis at 5 minutes versus 44.2% in the HM Email: [email protected] group, a difference of 48.2% (31.1%‐65.4%; P <.001 for noninferiority). There were Funding information no device‐related adverse events. Biom'up SA Conclusions: In this multicenter, randomized, controlled trial, comparison of CP to HM revealed CP superiority and noninferiority for TTTH at 3 and 5 minutes, respectively. KEYWORDS bleeding scale, collagen, hemostat, hemostatic agent, hemostatic combination powder, thrombin ------------------------------------------------------------------------------------------------------ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2019 The Authors. Journal of Cardiac Surgery published by Wiley Periodicals, Inc. J Card Surg. 2019;1–7. wileyonlinelibrary.com/journal/jocs | 1 2 | DANG ET AL. 1 | INTRODUCTION with minimal, mild, or moderate bleeding, assessed using a clinically validated bleeding severity scale.2 Despite advances in surgical techniques, excessive bleeding remains Patients were excluded from participation if they had a known a major complication associated with surgery and contributes to poor sensitivity or allergy to bovine and/or porcine substance(s) or any clinical outcomes.1 Conventional techniques for obtaining hemostasis other component(s) of the hemostatic agents, had religious or other during surgery include a variety of manual, mechanical, and thermal objections to porcine or bovine components or were not appropriate techniques. Local hemostatic agents may be used in cases where for inclusion in the trial per the medical opinion of the investigator. conventional techniques for hemostasis are either ineffective or impractical. Although the properties of the ideal local hemostatic agent may vary according to the surgical specialty, some properties 2.3 | Trial endpoints are universally valued including rapid and effective control of bleeding; ability to make effective contact with the bleeding surface; The primary endpoint of this trial was the superiority of CP relative acceptable safety profile; and ease of preparation and use. to HM for the proportion of subjects reaching hemostasis within The purpose of this study was to evaluate the performance of a 3 minutes. The secondary endpoint of this trial was the noninferiority recently approved, novel combination powder (CP) compared with an of CP relative to HM for the proportion of subjects reaching established, control hemostatic matrix (HM) in terms of total time to hemostasis within 5 minutes, utilizing a noninferiority margin of 10%. hemostasis (TTTH; the time from the start of device preparation until hemostasis was achieved). This endpoint captures a time most relevant for surgeons in terms of patient safety and efficiency as it 2.4 | Protocols reflects not only effective bleeding control but the ease of preparation as well. Patients were assessed preoperatively to obtain written informed consent for clinical trial participation, confirmation of preoperative eligibility criteria, and collection of demographic data and medical 2 | MATERIALS AND METHODS history. Enrollment and randomization were performed intraoperatively 2.1 | Trial design after confirmation of intraoperative eligibility criteria. Randomization occurred immediately following the identification of the TBS. This was a prospective, multicenter, randomized, controlled trial Subjects were randomized to CP or HM in a 1:1 ratio. To ensure evaluating the performance of a CP (HEMOBLAST Bellows; Biom’up, balance through time and to maintain concealment of the randomiza- France) consisting of collagen, chondroitin sulfate, and thrombin tion process, blocked randomization was performed using random compared to an HM (FLOSEAL Hemostatic Matrix; Baxter Health- block sizes of 2, 4, or 6. care Corporation, Hayward, CA). Hemostatic device performance and information regarding the This clinical trial was conducted in accordance with good clinical treated TBS were recorded intraoperatively. Patients were discon- practice (GCP, ICH E6) and 21 CFR Parts 50, 54, and 56. The trial tinued upon completion of the intraoperative visit. was registered on ClinicalTrials.gov (NCT #03725098). Institutional Baseline bleeding severity was assessed using a clinically Review Board (IRB) approvals and written informed consent from validated, quantitative surface bleeding severity scale (SBSS).2 each patient or patient’s legally authorized representative were Minimal, mild, and moderate bleeding severities—corresponding to obtained before any study‐specific activities being performed. The SBSS (SPOT GRADE) scores of 1, 2, and 3—were eligible for inclusion date of the first IRB approval was 19 December 2018. in study.2 TTTH was defined as the time from the start of device preparation, an indicator of when a surgeon asks for a surgical 2.2 | Eligibility criteria hemostat until hemostasis was achieved. Timing started at the opening of the device packaging and ran continuously until 3 and Subjects had to meet all eligibility criteria to be enrolled in the clinical 5 minutes. Bleeding severity and successful hemostasis were trial. Inclusion criteria were assessed preoperatively and intraopera- assessed at the 3‐ and 5‐minute time points using the SBSS. tively. Preoperative inclusion criteria included: subject undergoing a Successful hemostasis was defined as no bleeding (an SBSS score nonemergent cardiothoracic operation and subject or an authorized of 0). Investigators were trained and tested on the SBSS before the legal representative provided prior written consent for trial enrollment of subjects.2 participation. The intraoperative inclusion criteria included: subject Additional exploratory outcomes that were assessed intraopera- did not have an active or suspected infection at the surgical site; tively included: satisfaction on time and ease of hemostatic device subject in whom the Investigator was able to identify a target preparation; time of hemostatic device preparation; the incidence of bleeding site (TBS) for which any applicable conventional means for TBS rebleeding; and incidence of device‐related adverse events. hemostasis were ineffective or impractical; and subject had a TBS Satisfaction was rated on a 5‐point scale using the following DANG ET AL. | 3 definitions: 1 = dissatisfied, 2 = somewhat dissatisfied, 3 = neither analyses were performed using Power BI (Microsoft, Redmond, WA) satisfied or dissatisfied, 4 = somewhat satisfied, and 5 = satisfied. and R. Both the CP and HM devices were prepared and used according to their approved respective labeling. 3 | RESULTS 2.5 | Statistical analysis 3.1 | Study population Continuous endpoints were summarized using descriptive statistics, A total of 105 subjects were enrolled and randomized across four which included the number of subjects (n), mean and standard investigational sites in the United States consisting of both academic deviation. Categorical endpoints were summarized using frequencies and private practice institutions. Fifty‐three subjects were rando- and percentages. Two‐sample t tests and χ2 tests were used to test mized to the CP group and 52 to the HM group. differences in continuous and discrete baseline covariates between The average age of enrolled subjects was 63.7 years and the randomized groups, respectively. average body mass index (BMI) was 31.6 (obese). Age and BMI were The primary efficacy endpoint was defined as the difference in not significantly different between CP and HM treatment groups the probability of hemostasis at 3 minutes comparing CP to HM. (P =.323 and P =.364, respectively). There was more male than Letting θ denote the true difference in the probability of hemostasis female subjects enrolled, though the distribution of gender was not at 3 minutes between CP and HM, the trial tested the null hypothesis different between treatment groups (P =.120). There were no H0: θ < 0 vs the alternative hypothesis Ha: θ > 0 using a one‐sided significant differences in treatment groups in terms of ethnicity level 0.025 two‐sample binomial test of proportions with continuity and race. Subject demographics are presented in Table 1. correction. The corresponding Wald‐based 95% confidence interval Medical history was similar between treatment groups, with no (two‐sided) for the difference in probability of the TTTH at 3 minutes differences in the rates of concomitant illnesses and preoperative was also computed and reported. The secondary endpoint of TTTH anticoagulation regimen. The most common concomitant illnesses within 5 minutes was analyzed in an analogous fashion. Per protocol, included hypertension, hyperlipidemia, coronary artery disease, exclusion of a 10% difference in favor of HM would signify the heart failure, chronic kidney disease, arrhythmia, myocardial noninferiority of CP relative to HM. infarction, sleep apnea, chronic obstructive pulmonary disease, Significance testing for the primary and secondary hypotheses and anxiety. was performed in a hierarchical fashion to control the familywise The most frequent surgical procedure for enrolled subjects was type I error rate of the study. In this case, testing of the secondary coronary artery bypass grafting, followed by valve repair or endpoint would only have been conducted if statistical significance replacement. As shown in Table 2, the locations of the hemostat‐ were met for the primary endpoint. No adjustment for multiple treated TBS were similar between treatment groups (P =.350), with testing was performed for exploratory endpoints. All statistical the most common location being the sternum. The dimensions of the T A B L E 1 Baseline demographics for each treatment group Measure All CP HM P value a Age, y 63.7 ± 11.7 (57.8, 71.2) 62.6 ± 11.4 (57.8, 71.1) 64.9 ± 12.1 (58.0, 73.7).323 Genderb.120 Male 81/105 (77.1%) 37/53 (69.8%) 44/52 (84.6%) Female 24/105 (22.9%) 16/53 (30.2%) 8/52 (15.4%) Ethnicityb.083 Hispanic or Latino 10/105 (9.5%) 8/53 (15.1%) 2/52 (3.8%) Not Hispanic or Latino 94/105 (89.5%) 44/53 (83.0%) 50/52 (96.2%) Missing 1/105 (1.0%) 1/53 (1.9%) 0 (0.0%) Raceb.480 Caucasian 49/105 (46.7%) 27/53 (50.9%) 22/52 (42.3%) African American 10/105 (9.5%) 4/53 (7.5%) 6/52 (11.5%) American Indian or Alaska native 0/105 (0.0%) 0/53 (0.0%) 0/52 (0.0%) Asian 24/105 (22.9%) 9/53 (17.0%) 15/52 (28.8%) Native Hawaiian or other Pacific Islander 13/105 (12.4%) 7/53 (13.2%) 6/52 (11.5%) Other 9/105 (8.6%) 6/53 (11.3%) 3/52 (5.8%) BMI, kg/m2a 31.6 ± 30.5 (25.0, 31.6) 28.8 ± 6.6 (24.0, 31.9) 34.3 ± 42.8 (25.1, 30.6).364 Abbreviations: CP, combination powder; HM, hemostatic matrix. a Reported as mean ± standard deviation (p25, p75). b Reported as n/N (%). 4 | DANG ET AL. T A B L E 2 Surgical procedure and baseline TBS characteristics for treatment group Measure CP HM P value Target bleeding site location.350 Aorta 1/53 (1.9%) 0/52 (0.0%) Aortic cannulation site 1/53 (1.9%) 2/52 (3.8%) Aortotomy 1/53 (1.9%) 0/52 (0.0%) Ascending aorta 6/53 (11.3%) 3/52 (5.8%) Left atrium 1/53 (1.9%) 0/52 (0.0%) Right atrium 3/53 (5.7%) 2/52 (3.8%) Sternum 27/53 (50.9%) 25/52 (48.1%) Venous anastomosis site 0/53 (0.0%) 4/52 (7.7%) Other 13/53 (24.5%) 16/52 (30.8%) TBS approximate dimensions, cm2 4.2 ± 6.6 3.1 ± 4.8.321 (1.0, 6.0) (1.0, 2.4) Conventional procedures for hemostasis.140 Cautery 0/53 (0.0%) 2/52 (3.8%) Cautery and pressure 4/53 (7.5%) 4/52 (7.7%) None practical 34/53 (64.2%) 33/52 (63.5%) Pressure 6/53 (11.3%) 2/52 (3.8%) Suture 7/53 (13.2%) 11/52 (21.2%) Missing 2/53 (3.8%) 0/52 (0.0%) Abbreviations: CP, combination powder; HM, hemostatic matrix; TBS, target bleeding site. TBS were similar between treatment groups (P =.321), as were the The secondary efficacy endpoint was also met, with 92.5% of the conventional procedures for hemostasis (P =.140). CP group achieving hemostasis vs 44.2% in the HM group, a The baseline SBSS scores, provided in Table 3, were not difference of 48.2% (31.1%‐65.4%; P <.001 for noninferiority). significantly different between treatment groups (P =.340). In addition, the proportion of CP vs HM subjects hemostatic at 3 and 5 minutes by baseline bleeding severity (minimal, mild, or moderate) was significantly different, as presented in Table 5 and 6. 3.2 | Primary and secondary endpoints The proportion of subjects in each treatment group that achieved 3.3 | Exploratory outcomes hemostasis at 3 and 5 minutes is shown below in Table 4 and Figure 1. The CP group had a higher proportion of subjects achieving The average satisfaction ranking was 4.8 ± 0.6 for the CP hemostasis at each time point assessed. group, compared with 3.5 ± 1.5 for the HM group, which was The primary efficacy endpoint for the superiority of CP relative statistically significant (P <.001). The mean preparation times were to HM for success at achieving hemostasis within 3 minutes was met, 19.5 ± 9.8 seconds for CP and 2 minutes and 26.4 ± 52.3 seconds for with 64.2% of the CP group achieving hemostasis at 3 minutes HM (P <.001). compared to 9.6% of the HM group, a difference of 54.54% (37.4%‐ 71.6%; P <.001 for superiority). 3.4 | Safety There were no reported device‐related adverse events in either T A B L E 3 Baseline SBSS score for each treatment group treatment group. However, there was a significant difference in the SBSS score CP* HM* P value incidence of rebleeding between treatment groups, with no cases in 0 0/53 (0.0%) 0/52 (0.0%).340 the CP group and 11 cases in the HM group (P =.001). 1 30/53 (57.7%) 23/52 (43.4%) 2 13/53 (25.0%) 18/52 (34.0%) T A B L E 4 The proportion of each treatment group achieving 3 9/53 (17.3%) 12/52 (22.6%) hemostasis at 3 and 5 minutes 4 0/53 (0.0%) 0/52 (0.0%) Time CP HM P value 5 0/53 (0.0%) 0/52 (0.0%) 3 min 34/53 (64.2%) 5/52 (9.6%)