Evaluation of Hemostatic Powder Efficacy 2021 PDF

Original Article Clinical and Applied Thrombosis/Hemostasi...

Original Article Clinical and Applied Thrombosis/Hemostasis Evaluation of the Safety and Efficacy of a Volume 27: 1-10 ª The Author(s) 2021 Novel Thrombin Containing Combination Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/10760296211017238 Hemostatic Powder Using a journals.sagepub.com/home/cat Historical Control Brian A. Bruckner, MD1, William D. Spotnitz, MD2,3 , Erik Suarez, MD1, Matthias Loebe, MD, PhD4, Uy Ngo, PA1, Daniel L. Gillen, PhD5,6, and Roberto J. Manson, MD3,7,8 Abstract This clinical study compares 2 hemostatic agents, a novel combination powder (CP) (HEMOBLAST™ Bellows) and an established polysaccharide starch powder (PP) (Arista™ AH) to assess the usefulness of CP. Retrospective comparative analysis of CP (July 2018 to July 2019, 68 patients) to PP (January 2011 to January 2013, 94 patients) in cardiothoracic patients was performed using linear regression models adjusting for age, sex, and procedure type for the endpoints: blood loss; protamine to skin closure time (hemostasis time); chest tube output and blood products required 48 hours postoperatively; ICU stay; postoperative comor- bidities; and 30 day mortality. 162 patients (108 M: 54 F) underwent 162 cardiothoracic surgical procedures including: trans- plantation (n ¼ 44), placement of ventricular assist device (n ¼ 87), and others (n ¼ 31). Use of CP compared to PP (Estimated Mean Difference [95% CI], P-value) produced significant reductions: blood loss (mL) (886.51 [1457.76, 312.26], P ¼ 0.003); protamine to skin closure time (min) (16.81 [28.03, 5.59], P ¼ 0.004); chest tube output (48 hrs, mL) (445.76 [669.38, 222.14], P < 0.001); packed red blood cell transfusions (units) (0.98 [1.56, 0.4], P ¼ 0.001); and postoperative comor- bidities (0.31 [0.55, 0.07], P ¼ 0.012). There were no differences in the ICU stay (4.07 [2.01, 10.15], P ¼ 0.188) or 30-day mortality (0.57 [0.20, 1.63], P ¼ 0.291). The use of CP in complex cardiothoracic operations resulted in improved hemostasis and significant clinical benefits in blood loss, transfusion requirements, morbidity, and time in operating room. Keywords hemostasis, combination hemostat, efficacy, safety, powder Date received: 28 February 2021; revised: 11 April 2021; accepted: 23 April 2021. Introduction 1 Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Complex cardiothoracic surgical operations remain subject to Houston, TX, USA 2 Department of Surgery, University of Virginia, Charlottesville, VA, USA the risks of bleeding as a result of the use of anticoagulation and 3 Department of Medical Affairs, Biom’Up France SAS, Lyon, France the cardiopulmonary bypass circuit required to perform these 4 Miami Transplant Institute, University of Miami Health System, Miami, FL, procedures as well as the multiple, possible sequelae of using USA 5 these modalities and the underlying pathology of each patient Department of Statistics, University of California at Irvine, Irvine, CA, USA 6 Department of Epidemiology, University of California at Irvine, Irvine, CA, including hepatic and renal dysfunction. The required combina- USA tion of anticoagulation and cardiopulmonary bypass is known to 7 Department of Surgery, Duke University, Durham, NC, USA impair the coagulation cascade, activate the fibrinolytic cascade, 8 Department of Mechanical Engineering and Materials Science, Duke Univer- reduce platelet function, incite an inflammatory reaction, and sity, Durham, NC, USA create hemodilution as well as potentially cause acidosis and Corresponding Author: hypothermia. All these factors create a coagulopathic substrate.1 William D. Spotnitz, MD, University of Virginia Health System, 2738 SW 92nd Thus, the risk of bleeding in complex cardiothoracic surgery Drive, Gainesville, FL 32608, USA. remains clinically significant and can contribute to: exposure Email: [email protected] Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Clinical and Applied Thrombosis/Hemostasis Table 1. Patient and Surgical Characteristics. Continuous Covariates 162 Paents Are Summarized as Mean (SD). Discrete Covariates are Summarized Complex Cardiothoracic Procedures as Frequency (%). Polysaccharide Combination starch powder powder (CP) Polysaccharide Powder (PP) Combinaon Powder (CP) Characteristic (PP) (N ¼ 94) (N ¼ 68) Applied Applied N=94 N=68 Age (yrs) 56.18 (11.76) 58.29 (12.29) Sex Female 30 (31.9%) 24 (35.3%) Male 64 (68.1%) 44 (64.7%) Procedure Type Tx 32 (34%) 12 (17.6%) Endpoints: VAD 47 (50%) 40 (58.8%) - Intraoperave blood loss Other 15 (16%) 16 (23.5%) - Protamine to skin closure me Intra-Operative - Use of intraoperave blood products Blood Loss (mL) 1980.85 (2035.37) 1012.06 (1310.83) - Amount of hemostac agent used Protamine to Skin closure 96.71 (29.58) 78.71 (41.19) - Chest tube output at 48 hours postoperavely (min) - Blood products required at 48 hours postoperavely PRBCs (units) 2.6 (2.4) 1.56 (2.08) - Length of stay in the ICU - 30-day morbidity and mortality FFPs (units) 2.07 (2.05) 0.44 (1.38) Platelets (units) 2.12 (1.73) 0.38 (0.88) Hemostatic Agent Used 2.46 (1.71) 2.12 (1.36) Figure 1. The study design compared 2 groups: a novel combination (units) powder (CP) hemostatic agent (HEMOBLAST™ bellows) and an Post-Operative – 48 hrs established polysaccharide starch powder (PP) hemostatic agent Chest Tube Output (mL) 1460.53 (586.93) 1054.87 (840.81) (arista™ AH). PRBCs (units) 2.15 (2.01) 1.19 (1.46) FFPs (units) 0.68 (1.4) 0.29 (0.75) to blood product transfusions;2 need for re-explorations for Platelets (units) 0.38 (0.72) 0.24 (0.63) Post-Operative – 30 days bleeding,3 prolonged lengths of intensive care unit and hospital Days in ICU 12.11 (12.13) 16.56 (25.14) of stay;3 increased morbidity and mortality;3 and larger hospital No. of Comorbidities costs.4,5 Greater patient acuity and procedural complexity as (30 days) characterized by the emerging use of aggressive antiplatelet 0 53 (56.4%) 45 (66.2%) therapy6 and the placement of mechanical assist devices 1 19 (20.2%) 21 (30.9%) (MCAD)7 may also contribute to increased risk of postoperative 2 20 (21.3%) 2 (2.9%) bleeding. In challenging surgical settings, hemostatic agents can 3 2 (2.1%) 0 (0%) Mortality be useful adjuncts to the armamentarium available to surgeons No 80 (85.1%) 62 (91.2%) for the control of bleeding8-12 and are known to be useful during Yes 14 (14.9%) 6 (8.8%) cardiothoracic surgical operations.13-15 Recently, a new powder has been added to the toolbox of available hemostatic agents.16 This study compares a novel combination powder (CP) hemo- confidentiality insured. The study design (Figure 1) is observa- static agent (HEMOBLAST™ Bellows, Biom’Up France SAS, tional in nature and utilizes the data available on all patients, Lyon, France)16 consisting of porcine collagen, bovine chondroi- sequentially sampled into a single surgical practice, over 2 tin sulfate, and human pooled plasma thrombin to an established cohort periods operated upon by senior members from an inter- plant derived, polysaccharide starch powder (PP) hemostatic nationally known group performing over 1600 cardiac opera- agent (Arista™ AH, Becton Dickinson/Bard, Warwick, RI, tions annually. The CP group consisted of patients undergoing USA)17 to assess the usefulness of CP. Although both hemostatic complex cardiothoracic procedures by 2 experienced surgeons agents are provided in the form of powders, the potential (more than 3 years in practice) without surgeons in training enhancements of CP include activation of platelets by collagen, adhesion of the wound to surrounding tissues by chondroitin from July 2018 until July 2019 (68 patients, Drs. Bruckner and sulfate, and conversion of fibrinogen to fibrin by thrombin. Suarez) and the comparator PP group consisted of patients undergoing complex cardiothoracic procedures by 2 experi- enced surgeons (more than 3 years in practice) without sur- Methods geons in training from January 2011 to January 2013 (94 patients, Drs. Brucker and Loebe), all at the same institution. Study Population Subjects were identified in 1of 4 ways: 1. Directly from our This retrospective, de-identified, single site study underwent practice or inpatient data; 2. Review of medical records within review and approval by the institutional review board (IRB) the HMH-Medical Center inpatient list (MethOD); Epic elec- of Houston Methodist Hospital (HMH) with patient tronic medical records; or archived medical records. The case Bruckner et al 3 Figure 2. Violin plots depicting the distribution of protamine to skin closure time in minutes for patients treated with combination powder (CP) and those treated with polysaccharide starch powder (PP). Plots are stratified by procedure type (transplant, VAD, and other). Dots within each violin plot depict observed data points. mix inclusion criteria were based on the clinical practice of a Morbidity included ventilator dependence (ventilator require- surgical heart failure service that predominantly performs com- ment > 7 days), renal failure (new onset requiring dialysis), plex heart failure procedures with high bleeding tendencies shock (hypotension requiring 2 or more pressors), sepsis (pos- including consecutive heart transplants, lung transplants, and itive blood cultures and hypotension), and stroke (verified by ventricular assist devices (VADs) as well as a small number of CT scan or MRI scan). coronary artery bypass graft (CABG) and valvular/aortic pro- cedures. Inclusion criteria included factors that are important to reduce perioperative bleeding: cessation of platelet inhibitors Surgical Technique (>5 days) as well as correction of anemia (Hgb < 8.0); hypo- All procedures were performed through a complete median thrombocytopenia (Plts < 60,000); and coagulopathy (PT/INR sternotomy except for lung transplants, that were performed > 15/1.5). All patients underwent cardiopulmonary bypass with through clamshell incisions. After weaning from cardiopul- the exception of 3 patients who required unplanned emergent monary bypass, heparinization was reversed by protamine sul- re-exploration for bleeding within 24 hours. fate. Thereafter, the powdered hemostatic agents were applied as specified in their instructions for use (IFUs).16,17 Application was performed encompassing the entire operative field to Study Endpoints address all instances of active bleeding persisting after employ- All patient records were stratified by age, sex, and complexity ing conventional means including direct pressure, electrocau- of the cardiothoracic surgical procedure. The endpoints mea- tery, and suture ligation. sured in this retrospective comparison consisted of both intrao- perative and postoperative elements. Intraoperative measurements included: blood loss; protamine to skin closure Statistical Methods time (hemostasis time); and amount of hemostatic agent used. The distribution of patient and procedure characteristics were Postoperative measurements included: chest tube output at 48 described using the sample mean and standard deviation for hours; blood products required; length of stay in the intensive continuous measures and the observed frequency and percent care unit (ICU); 30-day morbidity; and 30-day mortality. for discrete measures. Inferential comparisons of continuous 4 Clinical and Applied Thrombosis/Hemostasis Figure 3. Empirical density plots for number of intra-operative PRBCs for patients treated with combination powder (CP) and those treated with polysaccharide starch powder (PP). The upper left plot includes all data while the remaining 3 plots are stratified by procedure type (transplant, VAD, and other). intra- and post-operative outcome measures were compared 56.18 (11.76), respectively. There was an observed preponder- using multiple linear regression. Logistic regression was used ance of men compared to women in both groups. A similar to compare the probability of death between patients treated distribution of procedures was observed in both groups with with CP and those treated with PP as well as to examine the the most frequent procedure being placement of VADs. association between blood loss and mortality. In all regression Visual depictions of the distribution of intra- and analyses, we a priori adjusted for age, sex, and procedure type post-operative measures of interest comparing CP to PP are as potential confounding factors in the comparison between CP displays in Figures 2 to 5. After adjustment for age, sex, and and PP. Residuals diagnostics to assess departures from the procedure type, use of CP compared to PP (Estimated Mean assumption of homoscedasticity in linear regression models Difference [95% CI], P value) resulted in multiple significant and to assess influential data points were conducted. Any iden- intraoperative endpoint reductions (Table 2) using CP including: tified influential points could not be determined to have arisen blood loss (mL) (886.51 [1457.76, 312.26], P ¼ 0.003); from data entry error and were, hence, kept in all reported protamine to skin closure time (min) (16.81 [28.03, 5.59], analyses. Secondary sensitivity analyses omitting influential P ¼ 0.004); and amount of packed red blood cells (units) (1.10 points were also conducted but are not presented as results did [1.83, 0.37], P ¼ 0.003), fresh frozen plasma (units) (1.60 not qualitatively differ from the primary analysis. While all [2.18, 1.02], P < 0.001), and platelets (units) (1.73 [2.19, pre-specified analyses are presented, no adjustments for multi- 1.27], P < 0.001) transfused. There was no significant differ- ple comparisons have been made and inferential P values ence in the mean amount of intraoperative hemostatic agent used should be interpreted accordingly. All statistical analyses were (units) (0.37 [0.87, 0.13], P ¼ 0.154). Significant postopera- performed using R version 3.4.1. tive endpoint reductions at 48 hours included: chest tube output (mL) (445.76 [669.38, 222.14], P < 0.001); packed red blood cell transfusions (units) (0.98 [1.56, 0.4], P ¼ Results 0.001); and fresh frozen plasma transfusions (units) (0.38 Comparison of baseline demographics (age, sex, procedure [0.75, 0.01], P ¼ 0.044) as well as postoperative comorbid- type) between the CP and PP groups revealed no statistically ities (0.31 [0.55, 0.07], P ¼ 0.012). significant differences using a 2-sided level.05 test (Table 1). After adjustment for age, sex, and procedure type there were The mean ages of the CP and PP groups were 58.29 (12.29) and no significant differences between the 2 groups with respect to: Bruckner et al 5 Figure 4. Empirical density plots for number of intra-operative FFPs for patients treated with combination powder (CP) and those treated with polysaccharide starch powder (PP). The upper left plot includes all data while the remaining 3 plots are stratified by procedure type (transplant, VAD, and other). postoperative platelet transfusions (units) (0.15 [0.37, transfusion of packed red blood cells (units) and fresh frozen 0.07], P ¼ 0.181); postoperative days in the ICU (4.07 plasma (units); and postoperative comorbidities. [2.10, 10.15], P ¼ 0.188); and the odds of mortality within Postoperative days in the ICU and 30-day mortality esti- 30 days of surgery (OR ¼ 0.57 [0.20, 1.63], P ¼ 0.291). mated odds ratio did not reach statistically significant values. Secondary analyses considered the association between total There were, however, noted to be outliers in ICU days that had blood loss and 30-day mortality. After adjustment for age, sex, moderate influence on the large standard deviation for mean and procedure type it was estimated that each 500 mL of blood ICU days. As these outlying observations were not concluded loss experienced during surgery was associated with a 21% to result from data entry errors, they were retained in all anal- higher odds of mortality within 30 days (OR ¼ 1.21 [1.35, yses presented. Further, precision to estimate the association 3.35], P ¼ 0.008). with 30-day mortality is fairly low in the current study given There were no adverse events noted to be specifically asso- the total sample size and number of observed deaths. Intrao- ciated with the use of either CP or PP. perative blood loss was, however, found to be significantly associated with 30-day mortality and significant differences between CP and PP were seen with respect to blood loss. Discussion In addition, the observed differences in intraoperative The demographics of the 2 groups used for this comparison hemostatic agent use for CP and PP, in terms of numbers of were similar with respect to age, sex, and procedure type, units used (units) (0.37 [0.87, 0.13], P ¼ 0.154), are actu- thereby permitting reasonable comparison of specific end- ally even larger in terms of amount of powder used because CP points between the 2 retrospective groups. units contained 1.65 grams of powder and PP units contained 5 The endpoints reflecting the degree of bleeding associated grams of powder. After making calculations for the total with the cardiac surgical procedures in this report strongly amount of product used in grams, the estimated difference was supported improvements using CP. These statistically signifi- significantly less in the CP group compared to the PP group cant differences included, intraoperatively: blood loss (mL); (8.86 [11.01, 6.71], P < 0.001). Thus, it was observed that protamine to skin closure time (min); transfusion of packed red more than 2 or 3 times as much PP was needed compared CP. blood cells (units), fresh frozen plasma (units), and platelets The costs of clinically using the 2 different hemostatic powders (units); as well as postoperatively: chest tube output (mL); in this study, particularly when one considers the fact that 6 Clinical and Applied Thrombosis/Hemostasis Figure 5. Empirical density plots for number of intra-operative platelets for patients treated with combination powder (CP) and those treated with polysaccharide starch powder (PP). The upper left plot includes all data while the remaining 3 plots are stratified by procedure type (transplant, VAD, and other). almost 2 to 3 times as much AristaTM was required to be used as to reduce bleeding and mortality; 32 single or dual agent HEMOBLASTTM are similar or more expensive for AristaTM. antiplatelet therapy to maximize bypass graft patency, but However, as detailed costs were not tracked in either group, no increase postoperative bleeding;33-36 direct linkage of postopera- definitive, precise cost comparisons can be made and have not tive cardiac surgical bleeding with increased cost;4,5 safe and be provided. efficacious use of postoperative fibrinogen concentrates;37,38 The parameters measured in this study including transfusion role of patient blood management in reducing blood product requirements for a variety of blood components, chest tube transfusion and improving cardiac surgical outcomes;39,40 trans- output, and postoperative comorbidity and mortality are well fusion reductions associated with the use of prothrombin com- known measures of bleeding severity during cardiac surgical plex concentrate;41,42 morbidity associated with reoperation for operations.1,19 Protamine to skin closure represents the topical bleeding following cardiac surgery;3,43,44 methods of employing hemostasis time, since the heparin is reversed by the protamine thromboelastometry (ROTEM) during cardiac surgery;45,46 con- and has been previously used as a measure of hemostatic tribution of albumin/gelatin to postoperative bleeding;47-49 effectiveness.18 advantages of anticoagulation management using thromboelas- Previous authors have examined the retrospective perfor- tography (TEG) during cardiopulmonary bypass;50-52 benefit of mance of a powdered hemostatic agent18 as well as the pro- thrombin inhibitors for pediatric VAD anticoagulation;53,54 spective comparative performance of hemostatic agents reduction of postoperative blood loss using Unilastin as an including powders in cardiothoracic procedures.15,19-30 How- antifibrinolytic agent;55,56 and blood loss leading to multi- ever, to the best of our knowledge, this report presents the first system organ failure and hematologic complications following direct comparison of 2 powdered hemostatic agents during LVAD insertion.7,57 cardiac surgical procedures. The CP agent described in this study contains porcine col- Postoperative bleeding following cardiothoracic procedures lagen, bovine chondroitin sulfate, and human thrombin.16 The remains an important concern with multiple avenues of inves- collagen provides initiation of coagulation and platelet activity, tigation continuing to assess factors predisposing and poten- the chondroitin sulfate assists with adherence of the wound to tially influencing the severity of this adverse event. Recent surrounding tissues, and the thrombin adjunctively functions to areas of interest include: development of new antifibrinolytic enhance the conversion of fibrinogen to fibrin. CP is the only agents to reduce bleeding;31 measurement of platelet function currently commercially available, powdered hemostatic agent Bruckner et al 7 Table 2. Estimated Mean Difference in Intra- and Post-Operative The authors have noted several advantages to using a hemo- Outcomes Comparing Combination Powder (CP) to Polysaccharide static powder such as CP including: immediate availability Starch Powder (PP). Estimates Are Based on Separate Linear Regres- with essentially no required preparation eliminating time con- sion Models That Adjust for Age and Sex of the Patient as well as suming efforts by operating room staff to prepare the agent as Procedure Type. well as the possibility that pre-preparing the agent before the Est. mean diff (95% CI) case to save time would result in product waste if the agent is Outcome (CP – PP) P value not actually needed; ease of application to both local and large areas as the powder can be easily placed focally as well as to Intra-Operative Blood Loss (mL) 886.51 (1457.76, 315.26) 0.003 large surface areas; clear glaze like appearance of the product Protamine to Skin closure 16.81 (28.03, 5.59) 0.004 after hemostasis is achieved; and versatility permitting use in (min) both open and minimally invasive procedures using a 35 cm PRBCs (units) 1.10 (1.83, 0.37) 0.003 nozzle extension.58 FFPs (units) 1.60 (2.18, 1.02)