Economic and outcomes consequences of TachoSil®: a systematic review.

BACKGROUND: TachoSil(®) is a medicated sponge coated with human fibrinogen and human thrombin. It is indicated as a support treatment in adult surgery to improve hemostasis, promote tissue sealing, and support sutures when standard surgical techniques are insufficient. This review systematically analyses the international scientific literature relating to the use of TachoSil in hemostasis and as a surgical sealant, from the point of view of its economic impact.
METHODS: We carried out a systematic review of the PubMed literature up to November 2013. Based on the selection criteria, papers were grouped according to the following outcomes: reduction of time to hemostasis; decrease in length of hospital stay; and decrease in postoperative complications.
RESULTS: Twenty-four scientific papers were screened, 13 (54%) of which were randomized controlled trials and included a total of 2,116 patients, 1,055 of whom were treated with TachoSil. In the clinical studies carried out in patients undergoing hepatic, cardiac, or renal surgery, the time to hemostasis obtained with TachoSil was lower (1-4 minutes) than the time measured with other techniques and hemostatic drugs, with statistically significant differences. Moreover, in 13 of 15 studies, TachoSil showed a statistically significant reduction in postoperative complications in comparison with the standard surgical procedure. The range of the observed decrease in the length of hospital stay for TachoSil patients was 2.01-3.58 days versus standard techniques, with a statistically significant difference in favor of TachoSil in eight of 15 studies.
CONCLUSION: This analysis shows that TachoSil has a role as a supportive treatment in surgery to improve hemostasis and promote tissue sealing when standard techniques are insufficient, with a consequent decrease in postoperative complications and hospital costs.

Introduction

Hemorrhage is a normal physiologic response to a tissue lesion involving the vascular system, and can be caused by a topical or systemic medical or surgical intervention.1 The process of hemostasis is triggered when there is a leakage from the vascular bed and is followed by the process of coagulation, whereby a number of factors lead to formation of a clot which subsequently undergoes lysis via fibrinolysis.2,3 During bleeding, mechanical hemostasis can be achieved using traditional methods, such as manual pressure or tourniquets, compressive bandages, ligatures, sutures, clippings, or electrocautery by means of monopolar or bipolar electroscalpels.4

Newer systems for vascular synthesis and coagulation, however, use a combination of pressure (through the handpiece-forceps) and radiofrequency applied to the target tissues.5 Thus, hemostasis does not depend on thrombus formation in the proximal vessel, but is the result of fusion of collagen and elastin in the intimal part of the vessel, which creates permanent scarring.6 Broadly, these systems are divided in three categories, ie, hemostatic dressings, surgical sealants, and blood-derived local hemostatic agents.

Hemostatic dressings are medical devices that can be derived from plants (polysaccharides, cellulose-derived products), animals (collagen and gelatin), or minerals (zeolite, only removable surgically). Their mechanism of action is chemical and/or mechanical, and they promote platelet aggregation on the surface of the wound/cut, creating a substrate for the coagulation cascade. Surgical sealants are also medical devices and can be of synthetic or semisynthetic origin. In the presence of water, the sealant is polymerized and interacts with the coagulation cascade by an exclusively mechanical action.3 The introduction of local hemostatic products identified as topical drugs of human or animal origin is more recent.7,8 These products (eg, Artiss® [Baxter International Inc., Deerfield, IL, USA], Beriplast® [CSL Behring, King of Prussia, PA, USA], Evicel® [OMRIX Biopharmaceuticals Ltd, Nes-Ziona, Israel], Quixil® [OMRIX Biopharmaceuticals Ltd] TachoSil® [Takeda Austria GmbH, Linz, Austria], and Tisseel® [Baxter International Inc.]) have two mechanisms of action, ie, they either work on the coagulation cascade with a metabolic hemostatic action or have a mechanical action as adhesive hemostatic agents.

These different product categories sometimes have the same clinical indications, ie, some facilitate hemostasis while others facilitate hemostasis, promote sealing, and support sutures.3 TachoSil, for example, is an equine-derived collagen sponge coated on one side with human fibrinogen and human thrombin. It is indicated as supportive treatment in adults undergoing surgery to improve hemostasis, promote tissue sealing, and support suturing in vascular surgery where standard techniques are inadequate.7,8 Unlike other drugs, TachoSil does not have special storage requirements (temperature below 25°C) and is ready for use.

The studies reported in the literature regarding the efficacy of these new products are often flawed by methodological errors and not rigorously conducted.9 In general, the studies available are not controlled and have been carried out in a limited number of surgical areas, so although these products are very widely used in a number of scenarios in clinical practice, their use is generally off-label. Research and evaluation of their potential economic impact on health care systems is even more limited, which makes it difficult for decision-makers (ie, physicians and pharmacists) to make cost-effective choices in a contest of increasing sustainability of expenditure.

Materials and methods

The aim of this review was to analyze the international scientific literature relating to the use of TachoSil in hemostasis and as a surgical sealant, from the point of view of its economic impact. We therefore carried out a systematic review of the PubMed literature up to November 2013,10 and reviewed economic evaluations comparing one or more alternatives in terms of costs and/or consequences for health care systems.9,11 The scientific papers were screened and selected based on the following inclusion criteria: clinical and economic evaluation of cost of treatment alone, cost-effectiveness, cost-utility, cost-benefit, and publication in English. Abstracts and posters were felt to lack sufficient information and therefore were not considered for inclusion. The key search terms used were “TachoSil” and “cost(s)”, “economic(s)”, “pharmacoeconomics”, “outcome research”, “topical hemostatic agents”, “fibrinogen”, “thrombin”, “hemostatic agents”, “randomized clinical trial”, and “surgical hemostasis”. Papers were selected if they contained clinical data showing a clear impact on use of resources by health care system (National Health Service [NHS], health care funds or insurance), if TachoSil was compared with other options (ie, standard suturing techniques, medical devices, surgical sealants, other hemostatic products) to improve postoperative hemostasis, and if the consequences for length of hospital stay and postoperative complications were reported.

Results

The results of this systematic analysis are shown in Figure 1. Of 358 potential papers identified, 334 were excluded because they were not economic evaluations (n=143), included comparisons of drugs other than those considered in this review (n=115), or were published as case reports (n=8).

Figure 1

Flow diagram of the selection process to identify studies to be included.

Twenty-four scientific papers were identified for inclusion in the study, 13 of which (54%) were randomized controlled trials and nine (37%) were prospective cohort studies. The studies identified included a total of 2,116 patients, 1,055 of whom were treated with TachoSil. According to our selection criteria, the papers were grouped according to the following outcomes: decrease in time to hemostasis, reduction in length of hospital stay, and decrease in postoperative complications.10

Impact on time to hemostasis

Six of the selected papers were randomized controlled trials in patients undergoing hepatic, cardiac, or renal surgery.12–17 Time to hemostasis with TachoSil was less (1–4 minutes) than that using other techniques. In patients undergoing cardiac surgery, hemostasis was reached in 3 minutes in 75% of cases using TachoSil versus 33% with other techniques.14,15 In total, 609 patients were included, 295 of whom were treated with TachoSil. The differences in time to hemostasis were statistically significant in five of the six papers13–17 (Table 1).

Table 1

Time to hemostasis reduction: TachoSil versus other standard techniques

Author	Year	Countries	Design	Surgery	Sealing agents	Patient no	Time to hemostasis	Statistical difference (P-value)
Kakaei et al12	2013	Iran	Randomized clinical trial	Hepatic	TachoSilSurgicelGlubran 2	151515	3.0 min3.2 min2.6 min	P=0.43
Fischer et al13	2011	Germany, Austria, Denmark	Randomized clinical trial	Hepatic	TachoSilArgon coagulator	6059	3.6 min5.0 min	P=0.001
Bajardi et al14	2009	Italy	Randomized clinical trial	Cardiac	TachoSilStandard technique	1010	264±127.1 sec408±159.5 sec	P=0.02
Maisano et al15	2009	Germany, Denmark, Spain, France, Italy	Randomized clinical trial	Cardiac	TachoSilStandard technique	5960	After 3.6 min: 75%After 3 min: 33%	P<0.0001
Siemer et al16	2007	Germany, Austria, Belgium	Randomized clinical trial	Renal	TachoSilStandard technique	9293	5.3 min9.5 min	P<0.0001
Frilling et al17	2005	Germany	Randomized clinical trial	Hepatic	TachoSilArgon coagulator	5962	3.9 min6.3 min	P=0.0007

Abbreviations: min, minutes; sec, seconds.

Change in length of hospital stay

Length of hospital stay was reported by 15 of the selected papers (62% of the total number of studies screened), which were carried out in patients undergoing pulmonary, hepatic, kidney, cardiac, or gastric surgery. Seven studies (46%) were randomized controlled trials18–24 and eight were prospective cohort studies.25–32 These studies included 1,426 patients, 723 of whom were treated with TachoSil (Table 2). A decrease in the length of postoperative hospital stay (by 2.01–3.58 days) was found for patients treated with TachoSil when compared with those treated using standard techniques. It is interesting to note that the decrease in length of hospital stay was greater in TachoSil-treated patients undergoing gastric or hepatic surgery, who showed a mean reduction in hospital stay of 3.58 and 2.33 days, respectively. Eight (53%) of the 15 studies showed a statistically significant difference in favour of TachoSil. Further, two randomized controlled trials showed that use of TachoSil in pulmonary surgery generated savings in the range of 98.00–205.50 Euros per patient when compared with standard techniques.22,23

Table 2

Hospital stay length reduction: TachoSil versus standard technique

Author	Year	Countries	Design	Surgery	Sealing agents	Patient no	Hospital stay (days)	Statistical difference (P-value)
Filosso et al18	2013	Italy	Randomized clinical trial	Lung	TachoSilStandard technique	1311	6.99.5	P<0.001
Cormio et al24	2012	Italy	Randomized clinical trial	Kidney	TachoSilStandard technique	5050	2.75 (±1.78)5.15 (±1.74)	P<0.0001
Montorsi et al19	2012	Italy	Randomized clinical trial	Pancreatic	TachoSilStandard technique	145130	710	ns
Pilone et al20	2012	Italy	Randomized clinical trial	Gastric	TachoSilStandard technique	1515	6.57	ns
De Rosa et al25	2011	Italy	Prospective cohort	Hepatic	TachoSilStandard technique	1510	6.78.3	ns
Pavlik et al26	2011	Norway	Retrospective cohort	Pancreatic resection	TachoSilStandard technique	7348	5 (2–16)5.5 (2–35)	ns
De Stefano et al27	2011	Italy	Prospective cohort	Gastric	TachoSilStandard technique	2439	7.29.3	ns
Briceno et al28	2010	Spain	Prospective cohort	Hepatic	TachoSilStandard technique	5758	9.6±5.112.6±6.7	P=0.03
Marta et al21	2010	Germany, Austria, Denamark, Hungary, Italy	Randomized clinical trial	Lung	TachoSilStandard technique	148151	8 (1–36)9 (4–28)	P=0.35
Padillo et al29	2010	Spain	Prospective cohort	Pancreatic transplant	TachoSilStandard technique	3434	22.8±11.134.6±11.3	P=0.03
Rena et al30	2009	Italy	Prospective cohort	Lung	TachoSilStandard technique	3030	5.87±1.077.50±3.20	P=0.01
Anegg et al22	2008	Germany, Austria	Randomized clinical trial	Lung	TachoSilStandard technique	7577	6.207.7	P=0.01
Droghetti et al23	2008	Italy	Randomized clinical trial	Lung	TachoSilStandard technique	2020	11.00 (9–17)14.3 (8–57)	P=0.73
Onorati et al31	2008	Italy	Prospective cohort	Cardiac	TachoSilStandard technique	1118	6.2±0.48.9±3.3	P=0.01
Barranger et al32	2007	France	Prospective cohort	Breast	TachoSilStandard technique	1312	3.55.5	ns

Abbreviation: ns, no statistically significant difference.

Decrease in postoperative complications

Reduction in postoperative complications was assessed in 15 studies carried out in patients undergoing pulmonary, hepatic, kidney, cardiac, or gastric surgery. Eight studies (53%) were randomized controlled trials12,18,19,21–24,33 and six were prospective cohort studies.28–31,34,35 These studies included 1,470 patients, 738 of whom were treated with TachoSil (Table 3). Postoperative complications included air leaks (for lung surgery), intra- abdominal infections, asymptomatic lymphocele, pericardial complications, postoperative fistulas, and others.

Table 3

Reduction in postoperative complications: TachoSil versus other standard techniques

Author	Year	Countries	Design	Surgery	Sealing agents	Patient no	Postoperative complications	Statistical difference (P-value)
Air leaks (lung surgery)
Filosso et al18	2013	Italy	Randomized clinical trial	Lung	TachoSilStandard technique	1311	4.7/days air leaks10/days	P<0.001
Marta et al21	2010	Germany, Austria, Denmark, Hungary, Italy	Randomized clinical trial	Lung	TachoSilStandard technique	148151	Global: 32%Global: 58%	P=0.022
Rena et al30	2009	Italy	Prospective cohort		TachoSilStandard technique	3030	Global: 55%Global: 96%	P=0.03
Anegg et al22	2008	Austria, Germany	Randomized clinical trial	Lung	TachoSilStandard technique	7577	Day 1: 43.6 mL/minutesDay 1: 86.1mL/minutes	P=0.004
Droghetti et al23	2008	Italy	Randomized clinical trial	Lung	TachoSilStandard technique	2020	Global: 50%Global: 95%	P=0.001
Intra-abdominal infections
Padillo et al29	2010	Spain	Prospective cohort	Pancreatic transplant	TachoSilStandard technique	3434	0%32%	P=0.003
Development of asymptomatic lymphocele
Simonato et al33	2009	Italy	Randomized clinical trial	Prostate	TachoSilStandard technique	3030	5%19%	P=0.001
Pericardial complications
Onorati et al31	2008	Italy	Prospective cohort	Cardiac	TachoSilStandard technique	1118	0%33%	P=0.039
Postoperative fistulas
Montorsi et al19	2012	Italy	Randomized clinical trial	Pancreatic	TachoSilStandard technique	145130	62.00%68.00%	P=0.267
Pavlik et al26	2011	Norway	Retrospective cohort	Pancreatic resection	TachoSilStandard technique	7348	8.00%12.00%	P=0.487
Other complications
Kakaei et al12	2013	Iran	Randomized clinical trial	Hepatic	TachoSilSurgicelGlubran 2	151515	Postoperative bleeding: 0Postoperative bleeding: 33%Postoperative bleeding: 13.3%	P=0.04
Cormio et al24	2012	Italy	Randomized clinical trial	Kidney	TachoSilStandard technique	5050	Tract complication: 2%Tract complication: 25.5%	P<0.001
Buda et al34	2012	Italy	Case-controlled analysis	Vulvar/ovarian and breast cancer	TachoSilStandard technique	816	Lower drainage volume: 133 mLLower drainage volume: 320 mL	P<0.001
Briceno et al28	2010	Spain	Prospective cohort	Hepatic	TachoSilStandard technique	5758	Postoperative complications: 8%Postoperative complications: 21%	P=0.03
Tamasauskas et al35	2008	Lithuania	Prospective cohort	Neurosurgery	TachoSilStandard technique	2929	Postoperative cerebrospinal fluid leak: 13.8%Postoperative cerebrospinal fluid leak: 41.4%	P=0.02

Air leaks are common after pulmonary surgery, and can result in serious complications, such as empyema and a protracted hospital stay.36 Air leaks were reported to occur in up to 58% of lobectomy procedures, depending on the surgical technique used.37 Our review identified a 9%–45% decrease in air leaks in five studies (four of which were randomized) using TachoSil when compared with standard techniques.18,21–23,30

The literature screened showed that TachoSil plays a role in decreasing intraoperative complications and postoperative air leaks, in addition to other postoperative complications (Table 3). It is important to keep in mind that a decrease in complications translates into a reduction in length of hospital stay (Table 2). In 13 of the 15 papers we identified, TachoSil achieved a statistically significant reduction in the number of postoperative complications when compared with standard techniques.

Discussion

In the current health care scenario of increasing costs, evaluation of the potential benefits of any given treatment should take into account its cost-effectiveness in comparison with standard treatments as well as its medium-term and long-term effects on both clinical outcome and total health care costs.38 Systematic literature reviews identify, assess, and summarize the results of individual studies, and make these results available and more accessible to health care decision-makers.9 This review of the literature shows the relevance of TachoSil as a supportive treatment in surgery to improve hemostasis and promote tissue sealing when standard techniques are inadequate. Our findings are strengthened by the high number of studies screened (n=24), 54% of which were randomized controlled trials and included a total of 2,116 patients. A statistically significant difference in favor of TachoSil was found in eight of 15 (53%) screened studies for decreased length of hospital stay and in 13 of 15 (87%) for reduction in postoperative complications, with a consequent decrease in hospital expenditure. Similar results were reported in a previous systematic review of the literature addressing the economic impact of TachoSil,10 but the number of papers we reviewed (n=24) was much higher than that identified in the earlier review in 2011 (n=15). Our review highlights further the role of TachoSil in reducing hospital costs and postoperative complications in a larger number of patients.

Moreover, as confirmed by other systematic reviews, TachoSil also helps to decrease the number of blood transfusions required.7 From an economic point of view, the 4-minute decrease in time to hemostasis observed for TachoSil with respect to standard techniques translates into reduced theater time and less staff requirements per treated patient. Finally, TachoSil is very easy to store (room temperature, 3-year shelf-life) and use (no requirement for thawing). This makes it a reference product for comparison with other hemostatic drugs, such as Tisseel, Quixil, Evicel, or Artiss.3

This review has some limitations. Not all the selected studies were randomized controlled trials (54%) and the economic endpoint was generally secondary in the design of these studies. Moreover, no pharmacoeconomic simulation models were included. Such pharmacoeconomic studies would have helped decision-makers by highlighting the key elements for choice of the best topical hemostatic agent and surgical sealant and would also help clinicians in outlining prospective economic evaluations and in correctly quantifying the costs of treatment.39

Some health economists have criticized the value of systematic reviews for economic evaluations in the health care setting.40 When conducting a systematic search, it is possible that not all relevant studies are identified. On the other hand, as discussed by other researchers,38,40 search terms like “economic evaluation”, “economics”, and “cost” in studies can lead to identification of a number of studies which are potentially irrelevant to a systematic review.

Moreover, differences in study design and methodology make it extremely difficult to synthetize the studies identified in a coherent set. However, methods have now been developed to guide such reviews,9,41 and a large number of systematic reviews have been conducted in various therapeutic areas, including ischemic stroke,42 chronic obstructive pulmonary disease,43 and hepatitis B and C.44,45 In the future, our ability to identify which topical hemostatic agent or surgical sealant should be used in a particular patient will depend increasingly on the quality of information available regarding prevention of postoperative complications in clinical practice and, indirectly, on the possibility of optimizing the use of hospital services. High-quality information would be necessary to optimize total health expenditure and simultaneously improve patient quality of life.