Tranexamic acid is beneficial as adjunctive therapy in treating major upper gastrointestinal bleeding in dialysis patients

Miso Sabovic1,, Janez Lavre2 and Bojan Vujkovac2

1 University Medical Centre, Department for Vascular Diseases, Ljubljana and 2 Department of Nephrology and Dialysis, Slovenj Gradec General Hospital, Slovenia



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. In a pilot, non-randomized trial we tested the efficacy of tranexamic acid (TXA), a potent fibrinolytic inhibitor, as adjunctive therapy in standard treatment of major upper gastrointestinal bleeding in dialysis patients.

Methods. Twenty consecutive patients (12 male, eight female; 63±8 years) with 36 episodes of major upper gastrointestinal bleeding were included in the study. In 16 episodes of bleeding TXA was used (in a dosage of 20 mg intravenously, followed for the next 4 weeks by 10 mg/kg/48 h orally), whereas in 20 other cases of bleeding, TXA was not used. The decision to use TXA was left to the attending physician's clinical judgement, resulting in all the more severe cases of bleeding being treated with TXA.

Results. Treatment including TXA was shown to be beneficial (relative to cases not treated with TXA) in terms of decreasing the rate of early re-bleeding (in the first week, 0 vs 6, P<0.05), the rate of early and late re-bleeding (in the first month, 1 vs 8, P<0.05), the rate of repeated endoscopic procedures (in the first month, 1 vs 8, P<0.05) and the number of blood transfusions needed (in the first month, 1.4±1.3 vs 2.6±1.5 units, P<0.05).

Conclusions. The results of this pilot study suggest that TXA can be beneficial in the treatment of major upper gastrointestinal bleeding in dialysis patients. This remains to be definitely confirmed in a randomized study.

Keywords: dialysis; erosive gastritis; re-bleeding; tranexamic acid; treatment; upper gastrointestinal bleeding



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Bleeding is an important complication in dialysis patients. It is known that they exhibit an increased incidence of gastrointestinal bleeding that is attributed to both a higher incidence of lesions producing bleeding (particularly a high incidence of erosive gastritis) and to the well-known impairment of haemostasis [13]. The control of gastrointestinal bleeding is more difficult to achieve than with patients with normal renal function [13]. The impaired haemostasis plays an important role in the difficulties in stopping gastrointestinal bleeding. However, there is no specific treatment capable of efficiently correcting impaired haemostasis. Such a fast-acting specific treatment would certainly be of clinical relevance. Tranexamic acid (TXA), a potent inhibitor of the fibrinolytic system, might fulfil these criteria [4]. It was shown that TXA could rapidly (in a few hours) improve impaired haemostasis in dialysis patients [5] and, further, that it has a specific beneficial effect in these conditions [6,7]. This is achieved by TXA-induced reduction of the level of fibrinogen fragments, which contribute to platelet dysfunction by binding to their receptors [8]. Furthermore, TXA prevents the binding of plasminogen to fibrin in blood clots and the activation of plasminogen to active plasmin, thus stabilizing haemostatic clots [4]. We found TXA effective in controlling bleeding in cases of chronic bleeding from colonic angiodysplasias and spontaneous subdural and cerebral haematoma in dialysis patients [9,10]. The meta-analysis of several studies clearly showed that TXA reduces recurrent bleeding, the need for surgery and mortality in patients with normal renal function and upper gastrointestinal bleeding [11]. However, TXA is not widely used, probably due to general opinion not being in favour of its efficacy [11]. However, its role as an adjunctive treatment for upper gastrointestinal bleeding (in patients with normal renal function) is again being explored [12].



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Twenty consecutive patients (12 male, eight female; 63±8 years) with 36 episodes of major upper gastrointestinal bleeding were included in the study. All patients had been on dialysis for at least 1 year. The study was carried out in three centres with four collaborating physicians. Endoscopic examination was performed in all patients and confirmed the origin of bleeding to be in the upper gastrointestinal tract. Endoscopic sclerotherapy was performed in seven cases (all attempts were judged to be successful in terms of an immediate stop to bleeding), whereas in 29 episodes sclerotherapy was not possible due to the diffuse nature of the lesions. The decision to use or not to use TXA (Cyklokapron®, Pharmacia & Upjohn AB, Stockholm, Sweden) was left to the attending physician's clinical judgement. The physician's attitude was to use TXA in the more severe cases of bleeding. Severe bleeding was defined as bleeding needing at least 2 units of packed red blood cells [13]. All physicians judged to both use and not use of TXA in their cases included in the study. Patients received 20 mg TXA intravenously immediately, followed by 10 mg/kg/48 h orally for the next 4 weeks. TXA was used and dose adjusted for end-stage renal disease [14]. In the first week, all patients were treated with heparin-free dialysis, followed by low-heparin dialysis for 2 weeks. All patients were treated with proton pump inhibitors and antacids for at least 1 month. They were followed for 1 month with respect to the following end points: the rate of early re-bleeding (or continuing bleeding) present as haematemesis and/or melena (in the first week); the rate of early and late re-bleeding (in the first month); the rate of repeated endoscopic procedures related to re-bleeding (in the first month); the need for additional (after correction of initial blood loss) blood transfusions (in the first month).

The proportions of patients having tested variable in each group were compared by the {chi}2 test; the values of continuous variables were compared between the two groups by Student's t test. A difference was accepted as significant if it reached the level of P<0.05.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The two groups did not differ in age, gender, coagulation tests or platelet count (Table 1Go). Furthermore, no difference was found concerning endoscopic findings and the rate of endoscopic sclerotherapy (Table 2Go), and in the use of drugs increasing haemorrhagic risk. One patient in each group regularly used aspirin, whereas four and five patients had used non-steroidal anti-inflammatory drugs occasionally in the previous month in the groups treated and non-treated with TXA, respectively. No patient used anti-coagulants. No co-morbidities relevant to haemorrhagic risk were present in any patient.


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Table 1.  Comparison of age, gender, platelet count and coagulation tests for patients treated and not treated with TXA: a few patients were treated more than once

 

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Table 2.  Comparison of endoscopic findings and the rate of endoscopic sclerotherapy in bleeding episodes treated and not treated with TXA

 
TXA was used, according to the attending physician's clinical judgement, in 16 episodes of bleeding, whereas in 20 episodes it was not used. Analysis of data present at admission showed that, probably, the more severe cases of bleeding were treated with TXA (Table 3Go). In the bleeding episodes treated with TXA the patients had lower haemoglobin values and blood pressure and received more blood transfusions at admission (the difference almost reached statistical significance). The proportion of severe bleeding was, however, significantly higher in bleeding episodes treated with TXA.


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Table 3.  Comparison of haemoglobin values, blood pressure, amount of required transfusions and the rate of severe bleeding (≥2 units of packed red cells) in bleeding episodes treated and not treated with TXA

 
Bleeding episodes treated with TXA were compared with those not treated with TXA, with respect to rate of re-bleeding, repeated endoscopic procedures and the amount of blood transfused (Table 4Go). Treatment with TXA was beneficial, in that it decreased the rate of early re-bleeding (in the first week, 0 vs 6, P<0.05), the rate of early and late re-bleeding (in the first month, 1 vs 8, P<0.05), the rate of repeated endoscopic procedures (in the first month, 1 vs 8, P<0.05) and the number of blood transfusions needed (in the first month, 1.4±1.3 vs 2.6±1.5 units, P<0.05).


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Table 4.  Comparison of the rate of early re-bleeding, early and late re-bleeding, repeated endoscopy and number of units of transfused blood in bleeding episodes treated and not treated with TXA

 
No urgent surgical procedure was required for to stop bleeding, no death was observed as direct consequence of bleeding. No complications in terms of arterial or venous thrombosis or other side effects were observed during treatment with TXA.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The management of upper gastrointestinal bleeding in dialysis patients is an important clinical problem, which frequently cannot be treated as successfully as it can in patients with normal renal function. In the present study we have explored the potential beneficial effect of TXA, a potent fibrinolytic inhibitor, as adjunctive therapy to standard management. The bases for the potential effectiveness of TXA include its following activities: local inhibition of fibrinolytic activity in bleeding lesions and inhibition of fibrinolytic activity of pepsin [15,16], stabilization of haemostatic clots [4] and specific systemic improvement of haemostatic impairment [6]. Our study was designed as a non-randomized trial. Episodes of major upper gastrointestinal bleeding present as haematemesis and/or melena, with endoscopically confirmed origin in the upper gastrointestinal tract, were included. As expected, and in the line with previous reports, the majority of cases exhibited diffuse erosive gastric and/or duodenal lesions, which could not be effectively managed with endoscopic sclerotherapy. Erosive gastritis is 6-fold more frequent in dialysis patients than in the population with normal renal function [3]. The decision to use TXA was left to the clinical judgement of the attending physician, whose attitude was to use TXA in more severe bleeding. Thus, 16 episodes were managed with TXA and 20 episodes were not. After initial treatment, consisting of endoscopic procedures if possible, drugs and correction of anaemia, the following outcomes were followed: early and late re-bleeding, repeated endoscopic procedures, and transfusions of blood related to re-bleeding. TXA was shown to be beneficial in all these. The rate of re-bleeding observed in the group not treated with TXA was similar to that reported previously, confirming the problem of re-bleeding or continuation of bleeding in dialysis patients [13]. As our study was not randomized, bias in the allocation of patients could possibly affect the results. However, the fact that the two groups did not differ with respect to haemostatic disturbances and the use of anti-aggregatory and anti-coagulant agents, and that the cases allocated to treatment with TXA exhibited not less, but in fact, more severe bleeding, makes the conclusions of study less subject to potential bias. No complications or side effects were observed during treatment with TXA, which is in line with its reported safety [17].

In summary, despite the fact that our study was non-randomized, the observed significant efficacy of TXA in all end points suggests that this drug should be beneficial as adjunctive treatment to standard management of major upper gastrointestinal bleeding. A randomized trial, which is now underway, will clarify this conclusion.



   Notes
 
Correspondence and offprint requests to: Miso Sabovic, MD, PhD, Department for Vascular Diseases, University Medical Centre, Riharjeva 24, 1000 Ljubljana, Slovenia. Email: miso.sabovic{at}trnovo.kclj.si Back



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 11. 1.02
Accepted in revised form: 17. 1.03





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