SYSTEMATIC REVISION AND META-ANALYSIS OF · Real-world outcomes of hemostatic matrices in cardiac surgery. Journal of cardiothoracic and vascular anesthesia, 28(6), 1558-1565. INTRODUCTION

SYSTEMATIC REVISION AND META-ANALYSIS OFHEMOSTATIC MATRICES FOR BLEEDING CONTROL

VALLS M1, ALMAZÁN R1, FERNÁNDEZ R1, GAY JG1, ZANELA 002, SOSA C2, SÁNCHEZ D2, CABRA HA2

1. TECHNOLOGÍA E INFORMÁTICA PARA LA SALUD, MEXICO CITY, MEXICO 2. JOHNSON & JOHNSON MEDICAL MEXICO, MEXICO CITY, MEXICO

SYSTEMATIC REVISION AND META-ANALYSIS OF HEMOSTATIC MATRICES FOR BLEEDING CONTROL

VALLS M¹, ALMAZÁN R¹, FERNÁNDEZ R¹, GAY JG¹, ZANELA OO², SOSA C², SÁNCHEZ D², CABRA HA²1. TECNOLOGÍA E INFORMÁTICA PARA LA SALUD, MEXICO CITY, MEXICO 2. JOHNSON & JOHNSON MEDICAL MÉXICO, MEXICO CITY, MEXICO

on available information from the clinical trials. For those comparisons where means and standard deviations were used, cohort mean differences were assessed. Similarly, odds ratios (ORs) were used for those comparisons reporting the incidence/number of events, as literature suggests. (Deeks, 1998).

To address heterogeneity, this analysis considered random effects models while using the I2 statistic, as it allows to incorporate the former within the meta-analysis. Figures 2-7 show the Forest Plots for all considered indicators. All Forest Plots show no statistically-significant differences between the porcine and bovine hemostatic matrices for any of the considered indicators. Table 2 summarizes estimated ORs and mean differences (95% confidence intervals). Substantial (>50%) and small (<25%) heterogeneity was observed.

Table 2. Comparison results

*In these comparisons, outcomes were analyzed through mean differences.

CONCLUSIONSThis systematic review & meta-analysis of published literature shows there are no statistically-significant differences between the considered hemostatic matrices for the listed indicators. Both products have components, indications and application methods that yield similar safety and efficacy outcomes for the considered procedures. Both technologies could be used indistinctly for the considered surgical specialties, with product choice having no impact on clinical outcomes.

REFERENCES

1. David, G., Lim, S., Gunnarsson, C., Kocharian, R., & Roy, S. (2015). Similar patient outcomes yet different hospital costs between flowable hemostatic agents. Journal of medical economics, 735-745.2. Deeks, J. (1998). Odds ratios should be used only in case-control studies and logistic regression analyses. BMJ, 317-1155.3. Echave, M. (2014). Use of Floseal, a human gelatine-thrombin matrix sealant, in surgery: a systematic review. BMC Surgery.4. Gazzeri, R., Galarza, M., & Alfier, A. (2012). Safety biocompatibility of gelatin hemostatic matrix (Floseal and Surgiflo) in neurosurgical procedures. . Surgical technology international, 49-54.5. Higgins, J., & Green, S. (2011). Cochrane Handbook for Systematic Reviews of Interventions. Obtenido de http://handbook.cochrane.org/6. Landi, A., Gregori, F., Marotta, N., & Delfini, R. (2015). Efficacy, security, and manageability of gelified hemostatic matrix in bleeding control during thoracic and lumbar spine surgery: FloSeal versus surgiflo.7. Journal of Neurological Surgery Part A: Central European Neurosurgery.8. Nogueira, L., Katz, D., Pinochet, R., Kurta, J. M., & Coleman, J. A. (2008). Comparison of gelatine matrix‐thrombin sealants used during laparoscopic partial nephrectomy. BJU international, 1670-1674.9. Price, J. S., Tackett, S., & Patel, V. (2015). Observational evaluation of outcomes and resource utilization from hemostatic matrices in spine surgery. Journal of medical economics, 18(10), 777-786.10. Tackett, S. M., Calcaterra, D., Magee, G., & Lattouf, O. M. (2014). Real-world outcomes of hemostatic matrices in cardiac surgery. Journal of cardiothoracic and vascular anesthesia, 28(6), 1558-1565.

INTRODUCTIONIt is estimated that bleeding complications occur in approximately 30% of surgeries. (Echave, 2014) Excessive, uncontrolled surgical bleeding might lead to patient morbidity and mortality, as well as an increase in intra- and post-operative complications and hospital resource utilization, such as blood transfusions and additional length of stay, imposing a heavy clinical and economic burden. Thus, achieving hemostasis is critical to prevent the former complications and events, which might yield potential clinical and economic benefits for patients, surgeons, hospitals and payers.

Hemostatic matrices with human thrombin (Surgiflo™ & Floseal™) are well-known safe and effective products indicated as adjuncts to achieve hemostasis in surgical procedures, particularly when conventional techniques (sutures, cautery or ligature) are ineffective or impractical, or in situations where other hemostatic agents are not indicated due to the risk of damaging vital structures. Absorbable porcine (Surgiflo™) and bovine (Floseal™) gelatin matrices with thrombin have individually shown to be safe and effective hemostats in cardiovascular (CV), neuro-spine (SP) and urinary tract (UT) procedures. However, comparative safety and efficacy outcomes would result of the interest of multiple stakeholders for decision making.

OBJECTIVEThe objective of the present study was to evaluate Surgiflo™’s a nd F loseal™’s comparative safety and effectiveness, as well as additional outcomes, in CV, SP and UT procedures by performing a systematic review and meta-analysis of published literature.

METHODSA systematic search of current published literature on safety and effectiveness of hemostatic matrices was performed to identify studies or trials where a direct comparison between the porcine and bovine gelatin matrices would have taken place. Used methodology focused on the combined use of the following MeSH terms surgical hemostasis, and the following key words: gelatin thrombin hemostatic matrix, floseal, surgiflo, surgical hemostasis meta-analysis, clinical trials & reviews. PubMed, The Cochrane Library y MediGraphic were the searched databases to perform the search. Additional filters were used to guarantee the words Floseal™ & Surgiflo™ would appear either on the t itle or in the abstract. Inclusion criteria included publications in English and Spanish up to December 2015, randomized controlled trials (RCTs) or retrospective analyses.

A total of 94 relevant studies were found; from them all, a duplicate was found in any of the other searched databases. Afterwards, only those publications where both hemostatic matrices were compared were selected; additional exclusion criteria included case & control studies and pre-clinical data. At the end, 87 articles were excluded, and the remaining 7 were subject to a deeper revision; 6 publications met all inclusion criteria (39,660 patients). Figure 1 shows the diagram for the systematic literature revision.

Figure 1. Flow diagram, systematic revision of evidence.

Source: own ellaboration

All of the final studies were assessed, along with all shown variables & potential comparison basis between them. Thus, 6 indicators were identified for posterior comparison, with at least 2 studies providing data for each of the former (Table 1).

Table 1. Assessed comparisons

RESULTSOnce comparable data were pooled from the articles, they were meta-analyzed using specialized software RevMan v.5.3. Two types of analyses were performed, depending

Indicator Included studies

Blood transfusions(Nogueira, Katz, Pinochet, Kurta, & Coleman, 2008), (Tackett, Calcaterra, Magee, & Lattouf, 2014),

(David, Lim, Gunnarsson, Kocharian, & Roy, 2015), (Price, Tackett, & Patel, 2015)

Surgical / OR time(Tackett, Calcaterra, Magee, & Lattouf, 2014), (David, Lim, Gunnarsson, Kocharian, & Roy, 2015),

(Price, Tackett, & Patel, 2015)

Length of hospital stay (Tackett, Calcaterra, Magee, & Lattouf, 2014), (Price, Tackett, & Patel, 2015)

Major complications(Nogueira, Katz, Pinochet, Kurta, & Coleman, 2008) , (Tackett, Calcaterra, Magee, & Lattouf, 2014),


Minor complications(Nogueira, Katz, Pinochet, Kurta, & Coleman, 2008) , (Tackett, Calcaterra, Magee, & Lattouf, 2014),


Hemostasis in < 7 minutes

(Landi, Gregori, Marotta, & Delfini, 2015), (Gazzeri, Galarza, & Alfier, 2012)

Indicator Results, ORs M-H, Random. (95% CI)Blood transfusions 0.52 (0.23, 1.19)

Surgical / OR time -14.81 (-47.88, 18.26)*

Length of hospital stay 0.10 (-0.03, 0.24)*

Major complications 0.73 (0.26, 2.04)

Minor complications 1.09 (0.69, 1.73)

Hemostasis in < 7 minutes 0.88 (0.29, 2.66)

22 articles identified in PubMed

93 non-duplicated articles

6 revised articles

6 articles were included in the assessment

87 excluded articles due to non-comparative methodology,

language, case & control or pre-clinical study

72 articles identified in Cochrane Library

0 articles identified in Medigrahpic

1 repeated article








REFERENCES

























Surgical / OR time -14.81 (-47.88, 18.26)*







6 revised articles






1 repeated article

© 2017 Ethicon US, LLC.

SURGIFLO® Hemostatic Matrix Kit Essential Product Information (Made from Absorbable Gelatin Sponge, USP) with Thrombin

DESCRIPTIONSURGIFLO® with Thrombin (SURGIFLO® Hemostatic Matrix Kit) is intended for hemostatic use by applying to a bleeding surface.

ACTIONSWhen used in appropriate amounts SURGIFLO® is absorbed completely within 4 to 6 weeks.

INTENDED USE/INDICATIONSSURGIFLO®, mixed with thrombin solution, is indicated in surgical procedures (other than ophthalmic) as an adjunct to hemostasis when control of bleeding by ligature or other conventional methods is ineffective or impractical.

CONTRAINDICATIONS • Do not use SURGIFLO® in intravascular compartments because of the risk of embolization.

• Do not use SURGIFLO® in patients with known allergies to porcine gelatin.

• Do not use SURGIFLO® in closure of skin incisions because it may interfere with the healing of skin edges. This interference is due to mechanical inter position of gelatin and is not secondary to intrinsic interference with wound healing.

WARNINGS • SURGIFLO® should not be used in the presence of infection and should be used with caution in contaminated areas of the body.

• SURGIFLO® should not be used in instances of pumping arterial hemorrhage. SURGIFLO® will not act as a tampon or plug in a bleeding site.

• SURGIFLO® should be removed from the site of application when used in, around, or in proximity to foramina in bone, areas of bony confine, the spinal cord, and/or the optic nerve and chiasm because it may swell resulting in nerve damage.

• Excess SURGIFLO® should be removed once hemostasis has been achieved.

• The safety and effectiveness of SURGIFLO® for use in ophthalmic procedures has not been established.

• SURGIFLO® should not be used for controlling post-partum intrauterine bleeding or menorrhagia.

• The safety and effectiveness of SURGIFLO® has not been established in children and pregnant women.

• The blue flexible applicator tip should not be trimmed to avoid exposing internal guidewire.

• The white straight applicator tip should be trimmed away from the surgical area. Cut a square angle to avoid creating a sharp tip.

PRECAUTIONS • Safe and effective use of SURGIFOAM® Sponge has been reported in a published neurologic retrospective study involving 1700 cases in Europe. Safe and effective use in neurosurgery has not been proven through randomized, controlled clinical studies in the United States.

• SURGIFLO® is supplied as a sterile product and cannot be resterilized.

• SURGIFLO® should not be used for packing unless excess product that is not needed to maintain hemostasis is removed. SURGIFLO® may swell up to 20% upon contact with additional fluid.

• SURGIFLO® should not be used in conjunction with autologous blood salvage circuits.

• SURGIFLO® should not be used in conjunction with methylmethacrylate adhesives.

• In urological procedures, SURGIFLO® should not be left in the renal pelvis or ureters to eliminate the potential foci for calculus formation.

ADVERSE EVENTSA total of 142 patients received SURGIFOAM® Sponge during a clinical trial comparing SURGIFOAM® Sponge to another absorbable gelatin sponge. In general, the following adverse events have been reported with the use of absorbable porcine gelatin-based hemostatic agents:

• Gelatin-based hemostatic agents may serve as a nidus for infection and abscess formation and have been reported to potentiate bacterial growth.

• Giant cell granulomas have been observed at implant sites when used in the brain.

• Compression of the brain and spinal cord resulting from the accumulation of sterile fluid have been observed.

• Multiple neurologic events were reported when absorbable gelatin-based hemostatic agents were used in laminectomy operations, including cauda equina syndrome, spinal stenosis, meningitis, arachnoiditis, headaches, paresthesias, pain, bladder and bowel dysfunction, and impotence.

• The use of absorbable gelatin-based hemostatic agents during the repair of dural defects associated with laminectomy and craniotomy operations, has been associated with fever, infection, leg paresthesias, neck and back pain, bladder and bowel incontinence, cauda equina syndrome, neurogenic bladder, impotence, and paresis.

• The use of absorbable gelatin-based hemostatic agents has been associated with paralysis, due to device migration into foramina in the bone around the spinal cord, and blindness, due to device migration in the orbit of the eye, during lobectomy, laminectomy, and repair of a frontal skull fracture and lacerated lobe.

• Foreign body reactions, “encapsulation” of fluid, and hematoma have been observed at implant sites.

• Excessive fibrosis and prolonged fixation of a tendon have been reported when absorbable gelatin-based sponges were used in severed tendon repair.

• Toxic shock syndrome was reported in association with the use of absorbable gelatin-based hemostats in nasal surgery.

• Fever, failure of absorption, and hearing loss have been observed when absorbable hemostatic agents were used during tympanoplasty.

063756-161128

Indications and Usage

EVITHROM® Thrombin, Topical (Human) for Topical Use OnlyLyophilized Powder for Solution

EVITHROM® is a topical thrombin indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature or cautery) is ineffective or impractical.

EVITHROM® may be used in conjunction with an Absorbable Gelatin Sponge, USP.

Important Safety Information

• For topical use only.

• Do not inject.

• Apply EVITHROM® on the surface of bleeding tissue only.

• The amount of EVITHROM® required depends upon the area of tissue to be treated and the method of application. In clinical studies, volumes up to 10 ml were used in conjunction with Absorbable Gelatin Sponge.

• Do not use for the treatment of severe or brisk arterial bleeding.

• Do not use in individuals known to have anaphylactic or severe systemic reaction to human blood products. Hypersensitivity reactions, including anaphylaxis, may occur.

• There is a potential risk of thrombosis if absorbed systemically.

• May carry a risk of transmitting infectious agents such as viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite manufacturing steps designed to reduce the risk of viral transmission.

• The most common adverse reactions during clinical trial (reported in at least 2% of subjects treated with EVITHROM®) were prolonged activated partial thromboplastin time, increased INR, decreased lymphocyte count, prolonged prothrombin time and increased neutrophil count.

• None of the patients treated with EVITHROM developed antibodies to human thrombin or to human Factor V/Va. The clinical significance of these findings is unknown.

For complete indications, contraindications, warnings, precautions, and adverse reactions, please reference full package insert.One or more of the authors is a Johnson and Johnson employee. The article was funded by Johnson and Johnson Medical Devices.

071864-170426

INTRODUCTION It is estimated that bleeding complications occur in approximately 30% of surgeries. (Echave, 2014) Excessive, uncontrolled surgical bleeding might lead to patient morbidity and mortality, as well as an increase in intra- and post-operative complications and hospital resource utilization, such as blood transfusions and additional length of stay, imposing a heavy clinical and economic burden. Thus, achieving hemostasis is critical to prevent the former complications and events, which might yield potential clinical and economic benefits for patients, surgeons, hospitals and payers.


OBJECTIVE The objective of the present study was to evaluate Surgiflo™’s and Floseal™’s comparative safety and effectiveness, as well as additional outcomes, in CV, SP and UT procedures by performing a systematic review and meta-analysis of published literature.

METHODSA systematic search of current published literature on safety and effectiveness of hemostatic matrices was performed to identify studies or trials where a direct comparison between the porcine and bovine gelatin matrices would have taken place. Used methodology focused on the combined use of the following MeSH terms surgical hemostasis, and the following key words: gelatin thrombin hemostatic matrix, floseal, surgiflo, surgical hemostasis meta- analysis, clinical trials & reviews. PubMed, The Cochrane Library y MediGraphic were the searched databases to perform the search. Additional filters were used to guarantee the words Floseal™ & Surgiflo™ would appear either on the title or in the abstract. Inclusion criteria included publications in English and Spanish up to December 2015, randomized controlled trials (RCTs) or retrospective analyses.

CONCLUSIONS This systematic review & meta-analysis of published literature shows there are no statistically- significant differences between the considered hemostatic matrices for the listed indicators. Both products have components, indications and application methods that yield similar safety and efficacy outcomes for the considered procedures. Both technologies could be used indistinctly for the considered surgical specialties, with product choice having no impact on clinical outcomes.









REFERENCES

























Surgical / OR time -14.81 (-47.88, 18.26)*







6 revised articles






1 repeated article








REFERENCES

























Surgical / OR time -14.81 (-47.88, 18.26)*







6 revised articles






1 repeated article

A total of 94 relevant studies were found; from them all, a duplicate study was found in the databases searched, and it was removed. Afterwards, only those publications where both hemostatic matrices were compared were selected; additional exclusion criteria included case & control studies and pre-clinical data. At the end, 87 articles were excluded, and the remaining 7 were subject to a deeper review; 6 publications met all inclusion criteria (39,660 patients). Figure 1 shows the diagram for the systematic literature revision.

All of the final studies were assessed, along with all shown variables & potential comparison basis between them. Thus, 6 indicators were identified for further comparison, with at least 2 studies providing data for each of the former (Table 1).

RESULTSOnce comparable data were pooled from the articles, they were meta-analyzed using specialized software RevMan v.5.3. Two types of analyses were performed, depending on available information from the clinical trials. For those comparisons where means and standard deviations were used, cohort mean differences were assessed. Similarly, odds ratios (ORs) were used for those comparisons reporting the incidence/number of events, as literature suggests. (Deeks, 1998).

To address heterogeneity, this analysis considered random effects models while using the I2 statistic, as it allows to incorporate the former within the meta-analysis. Figures 2-7 show the Forest Plots for all considered indicators. All Forest Plots show no statistically- significant differences between the porcine and bovine hemostatic matrices for any of the considered indicators. Table 2 summarizes estimated ORs and mean differences (95% confidence intervals). Substantial (>50%) and small (<25%) heterogeneity was observed.

Figure 2. Forest Plot – blood transfusions

Figure 3. Forest Plot – surgical / OR time

Figure 4. Forest Plot – length of hospital stay

Figure 5. Forest Plot – major complications

Figure 6. Forest Plot – minor complications

Figure 7. Forest Plot – hemostasis in < 7 minutes




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SYSTEMATIC REVISION AND META-ANALYSIS OF · Real-world outcomes of hemostatic matrices in cardiac surgery. Journal of cardiothoracic and vascular anesthesia, 28(6), 1558-1565. INTRODUCTION