Tranexamic Acid to Prevent OpeRation in Chronic Subdural Hematoma
Paraules clau
Resum
Descripció
1. INTRODUCTION AND RATIONALE Chronic subdural hematoma (cSDH) is a frequently occurring neurological disease of the elderly and common in daily neurosurgical practice. It consists of an extracerebral encapsulated collection of mostly liquefied old hematoma, located between the dura and arachnoid. The original small, and often asymptomatic, haemorrhage is caused by rupture of a bridging vein after, often minor, head trauma. Due to generalized cerebral atrophy, increased venous fragility, and the more frequent use of anticoagulation therapy, older people are more at risk of developing a cSDH.
During several weeks, the original hematoma is encapsulated by a membrane consisting of weak neocapillaries from where recurrent small bleedings occur. The pathophysiological mechanism is thought to be a problem in the local haemostasis due to fibrin degradation products of the original small hematoma that inhibit further haemostasis in the subdural space. Together with an osmotic draw of water, owing to its high protein content, this results in growth of the hematoma. Therefore, it usually takes several weeks for the cSDH to grow and become symptomatic.
Signs and symptoms arise due to compression of brain tissue. These can be generalised, such as headaches, light-headedness, cognitive disturbances, apathy, somnolence, seizures, frequent falling and depression. Also focal deficits, such as dysphasia, motor weakness or sensory disturbances, can be symptoms of a cSDH.
The current incidence of cSDH is estimated to be 15/100,000 per year. The number of patients with cSDH is expected to increase considerably in the near future due to the continuing growth of the elderly population, and the increase in the use of anticoagulation and anti-aggregation therapy. By 2030, the incidence is expected to rise up to 20/100,000 per year, thus making cSDH the most common neurosurgical condition in adults. In The Netherlands, this comes down to 3,600 new patients each year.
Treatment Treatment options are conservative and surgical. Conservative treatment currently consists of a wait-and-scan policy in which the patient is regularly monitored for neurological deterioration and growth of the hematoma on follow-up imaging. Anticoagulation and antiplatelet therapy is discontinued in low-risk patients, based on individual risk-benefit assessment and the discretion of the treating physician. If the clinical condition of the patient worsens, the indication for surgical evacuation of the hematoma is re-evaluated.
Spontaneous resolution of cSDH with a conservative treatment occurs in approximately 2.5% of patients, and is therefore relatively rare. Of all patients diagnosed with cSDH in The Netherlands, about 50% is primarily treated conservatively. Of these, around 75% still need an operation (own data). If the symptoms are serious or worsen over time, surgical evacuation of the hematoma is currently the designated therapy. This therapy is an effective treatment, but is also associated with life-threatening risks. In these old, often frail, patients with multi-comorbidity, surgery comes with significant risks for future cognitive functioning and, therefore, loss of independency. In a large series of 1205 patients, symptomatic recurrence after surgery was 9%, mortality 2% and unfavourable functional outcome 22%.
Outcome measurement Studies evaluating quality of life and functional outcome with cSDH patients are scarce. The modified Rankin Scale (mRS) score is usually the only clinical outcome parameter. A literature search for quality of life in cSDH results in only two clinical studies. The first used the postoperative mRS, Barthel Index and Sickness Impact Profile as outcome measurements; the second used a pre- and postoperative Karnofsky Performance Score.
Tranexamic acid As hyperfibrinolysis is thought to play a role in the liquefaction and enlargement of cSDH, pharmaceutical options to block fibrinolysis have been explored in an effort to eliminate the necessity for surgery. The use of tranexamic acid (TXA), an antifibrinolytic drug, has so far been reported in five small series. In the first retrospective series, a total of 21 patients were treated with TXA, of whom three after primary burr hole surgery. In none of these 21 patients, additional surgery was necessary. The second, a prospective pilot study in 14 patients, showed a 41% reduction of cSDH after surgery, and an additional 91% residual volume reduction on CT after 90 days, during oral TXA treatment of 650 mg per day, for a mean (SD) duration of 90 (27) days, without recurrence, re-expansion, or any complicating venous thromboembolisms. The third study, a case report series of three patients treated with 650mg TXA per day for one month after surgery for cSDH, showed no recurrences and thromboembolic complications. The fourth, a case report of one patient successfully treated primarily with TXA, was recently published, and finally, in the abstract of a Asian article, the authors conclude that administration of Gorei-San, a Japanese herbal Kampo medicine, combined with TXA has the potential to prevent recurrences of cSDH.
With these limited, however promising, data no definitive conclusion can be made regarding the role of TXA in the treatment of cSDH. Therefore, a prospective study evaluating the efficacy and safety of TXA is needed. Currently, two prospective trials (the TRACS study and the TRACE study are running in an effort to answer this question. The first study, a phase 2b trial with the aim to provide preliminary data required to plan a larger phase III trial, excludes patients using anticoagulants. These patients comprise a significant portion of the cSDH patient population, and therefore, the results of the TRACS study will be difficult to extrapolate to the future care of all cSDH patients. The second study (TRACE) is a randomised, observer blinded trial, investigating the value of treating cSDH patients with TXA after surgery. This is a different patient population than proposed in the investigators' trial, in which they plan to include only patients in whom the primary treatment is conservative. Also, both trials are set up with a primary radiological outcome parameter and therefore potentially provide insufficient clinically relevant information.
This phase III trial aims to investigate the efficacy and safety of TXA as an addition to a primary conservative treatment of cSDH, in an effort to prevent surgery for cSDH. Since surgical treatment under general anaesthesia and a hospital admittance of a minimum of two days is associated with significant morbidity, as described earlier, the investigators assume that preventing surgery also prevents deterioration of patients' quality of life. This trial is also the first in describing functional outcome and quality of life of cSDH patients in a prospective manner. Since the target population partially comprises patients with a depressed level of consciousness, and patients using anticoagulants and antiplatelets, these patient groups will be included in this trial as well.
Dates
Darrera verificació: | 11/30/2019 |
Primer enviat: | 06/18/2018 |
Inscripció estimada enviada: | 07/08/2018 |
Publicat per primera vegada: | 07/10/2018 |
Última actualització enviada: | 12/10/2019 |
Publicació de l'última actualització: | 12/12/2019 |
Data d'inici de l'estudi real: | 06/18/2018 |
Data estimada de finalització primària: | 09/19/2021 |
Data estimada de finalització de l’estudi: | 12/30/2022 |
Condició o malaltia
Intervenció / tractament
Drug: Tranexamic Acid
Drug: PLACEBO
Fase
Grups de braços
Braç | Intervenció / tractament |
---|---|
Active Comparator: Tranexamic Acid Tranexamic acid 500mg two times a day orally for a total of 28 days | Drug: Tranexamic Acid orally twice daily for 28 days |
Placebo Comparator: PLACEBO Placebo capsules two times a day orally for a total of 28 days | Drug: PLACEBO Oral placebo capsule two times a day for a total of 28 days |
Criteris d'elegibilitat
Edats elegibles per estudiar | 50 Years Per a 50 Years |
Sexes elegibles per estudiar | All |
Accepta voluntaris saludables | Sí |
Criteris | Inclusion Criteria: - On CT confirmed cSDH - Primary conservative treatment, based on clinical symptoms: Glasgow Coma Scale score >=14, mNIHSS score <=4 and a stable neurological deficit (no new, or progression of, symptoms between the assessment by the neurologist and the assessment by the neurosurgeon). Exclusion Criteria: Primary surgical treatment based on one or more of the following symptoms or parameters: medically intractable headache, midline shift >10mm, imminent death within 24 hours; - Structural causes for subdural haemorrhage, e.g. arachnoid cysts, cortical vascular malformations and a history of cranial surgery <1year; - Aneurysmal subarachnoid haemorrhage; - Active treatment for deep vein thrombosis, pulmonary embolism or cerebral thrombosis (secondary prophylaxis is not considered to be active treatment); - Active intravascular clotting or disseminated intravascular coagulation; - Known hypersensitivity or allergy to TXA or to any of the ingredients; - History of a blood coagulation disorder (hypercoagulability disorder); - History of severe impairment of renal function (eGFR <30ml/min or serum creatinine >150μmol/L); - History of anaemia (haemoglobin <6mmol/L); - History of convulsions; - History of inability to safely swallow oral medication. - Inability to obtain informed consent from the patient or legal representative (when the patient has a depressed level of consciousness as described in paragraph 11.2), including language barrier; |
Resultat
Mesures de resultats primaris
1. surgery for cSDH [within 12 weeks after start of treatment]
Mesures de resultats secundaris
1. cSDH volume [at four, eight and 12 weeks]
2. neurological impairment [at four, eight and 12 weeks]
3. falling incidents [during the 12 week study period]
4. cognitive functioning [at four, eight and 12 weeks]
5. performance in activities of daily living [at 12 weeks]
6. functional outcome [at 12 weeks]
7. patient health status [at 12 weeks]
8. mortality rate [at 12 weeks]
9. use of care [during the 12 week study period]
10. performance in activities of daily living [at 12 weeks]
11. health-related costs [during the 12 week study period]
12. patient health status [at 12 weeks]