Systematic Review On Association Between Warfarin And Subdural Haemorrhage

Methodology

Blood often gets accumulated in localised regions, outer the blood vessels, resulting in a medical condition, commonly referred to as subdural hematoma. The inner layers of the arachnoid ad the dura mater get filled with blood, and occur due to wear and tear of the veins that span the subdural space. Subdural hematoma has been closely linked to an elevation in the intracranial pressure that results in compression and damage of neuronal tissue that subsequently develops in to life threatening conditions¹. 1.7 million cases of traumatic brain injuries occur annually in the United States, of which 275,000 cases result in patient hospitalisation and 52,000 cases lead to death². There are several chemical agents, referred to as blood thinner or anticoagulants that lower blood clotting rates. Some of the most commonly used blood thinners are warfarin, aspirin and heparin. There lies a perception that anticoagulant therapies are associated with increased bleeding risks³. Although the anticoagulants are commonly used for the treatment of myocardial infarction, coronary artery disease, restenosis, and pulmonary embolism, they have been associated with greater risks of intracranial haemorrhage, the most prevalent of which is subdural hematoma. This article contains a systematic review that will discuss the association between warfarin and subdural haemorrhage, in comparison to other anticoagulants.

The evidence-based PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) tool was employed for the systematic review, which in turn established substantial transparency in the article selection. Several databases were used for retrieving the articles that principally encompassed prospective and retrospective cohort studies. The inclusion of articles was based on the PICO method that acted as a framework for formulating the research question. The population under consideration comprised of adults and older adults under anticoagulation therapy. Intervention of interest was warfarin as the principle blood thinner. This was compared with to other antithrombotic agents. The immediate and long lasting effects of warfarin and other anticoagulants such as aspirin and heparin were evaluated on several aspects that encompassed clinical outcomes and quality of life, internalised normalised ratio, and effect of resumption of anticoagulation agents on the risks of subdural haemorrhage. The systematic review was based on a three step search strategy. Specific key terms and phrases such as, anticoagulants, warfarin, intracranial pressure, subdural hematoma, bleeding, and subdural haemorrhage were fed as input in the databases CINAHL, MEDLINE, Embase, Cochrane Library, PubMed, Joanna Briggs Institute EBP database, and Scopus, among many others. The user guidelines published by the Joanna Briggs Institute was used for appraising the quantitative evidences. Use of the critical appraisal tool helped to establish validity of the systematic review. Only articles that met the criteria specified in the critical appraisal tool were included in the review. Certain factors that were taken into consideration during the appraisal of the articles include the fact whether all participants were equal at the beginning of the study, use of reliable and valid tools for outcome measurements, mention about elimination of confounding variables and use of reliable exposure tools.

Results

The schematic diagram given below depicts the steps that were undertaken for retrieval of articles that have been included in the systematic review. 340 articles were obtained in the initial hits after searching the databases mentioned above with the pre-decided key phrases. Following extraction of these 340 articles, several duplicates were removed that resulted in 101 articles, all of which were screened for their titles and abstracts. 58 articles were not relevant to the research and were excluded. Of the 43 articles that were reviewed for their full text eligibility, only 9 could be retrieved for inclusion in the review. Quantitative cohort studies that contained information on patients under pre-operative and post-operative antiplatelet or antithrombotic medications, with intracranial haemorrhage or subdural haematoma were selected. The population of patuents that was taken into consideration for the review included adults and older adults, under anticoagulation therapy. This approach of systematic review helped in summarising the results of the extracted healthcare cohort studies and presented high level of evidence regarding the effectiveness of the intervention (anticoagulation).

Figure 1- PRISMA chart showing number of articles included in the review

The PRISMA, commonly referred to as Preferred Reporting Item for Systematic Review and Meta-Analysis, helped in including quantitative articles and the systematic review. Most of the articles that were included in the systematic review were of a cohort or longitudinal nature, which were performed in cross sections at intervals, over time. All the studies included in the systematic review were found to illustrate the occurrence of acute subdural hemorrhage, and intracranial hemorrhage, following anticoagulation therapy treatment that encompassed administration of warfarin or other anticoagulant. Inclusion of the studies helped in achieving the research objective of investigating the link or association between administration of anticoagulant among patients and their susceptibility of facing high intracranial pressure that subsequently lead to subdural haematoma. Oral administration of Vitamin K antagonist leads to various health complications. All the studies were based on previous findings that had established close associations with intracranial haemorrhage and Vitamin K antagonist therapy. Uses of all the studies helped in identification of several themes that are mentioned below:

The internalised normalised ratio is most often used for calculating prothrombin time with respect to subdural haematoma that is associated with usage of anticoagulant. Retrospective study that focused on 69 patients suffering from subdural hematoma linked with warfarin administration, and 197 patients suffering from the condition not under warfarin medication focused on assessing expansion of the haematoma. Radiology reports were analysed for noting the enlargement among patients in the warfarin group, and they failed in remembering history of their trauma⁴. The group corresponding to HD1 INR 0.8-1.3 demonstrated an increased rate in the mean internalized normalised ratio along with radiographic expansions, in an estimated 22.5% patients. 20% patients in the other group HD1 INR 1.31-1.69, showed radiographic expansions. The effects of time to INR were also evaluated in another study that focused on haemorrhage among patients having undergone traumatic brain injury, under anticoagulant therapy⁵. Initial INR was demonstrated to be more than 2.0 among the patients who showed positive CT scan tests for subdural haemorrhage. Mean INR was found to take approximately 13.3 ± 10.5 hours reversal time below 1.5. While 49 patients could reach this mean INR in less than 10 hours, only 14 could do so in less than 5 hours. Reversal of INR in the group less than 5 hours also did not show any significant association with intracranial haemorrhage evolution. Differences for objects observed in mean INR among patients with good or poor outcomes by as much as 0.07, in a study that measured effects of preoperative anticoagulation on subdural hemorrhage. Values of INR versus among patients with mRS ≤ 1, in comparison to those having suffered subdural haemorrhage and with mRS > 1⁶. INR values <1.5 also found among intracranial haemorrhage patient had received prothrombin complex concentrates after an hour of its infusion⁷. These findings help in establishing the differences that exist in rates of INR among subdural haemorrhage patients underwater in medication when compared to other anticoagulants.

Discussion

The length of hospitalization, clinical outcome, functional outcome, mortality rates and quality of life of patients undergoing anticoagulant therapy, after subdural haematoma, were investigated by various studies. Effects of oral anticoagulation or warfarin were investigated in a retrospective cohort study that encompassed 94 cases. 22 patients under warfarin administration had been found to report low mean discharge Glasgow Outcome Scale scores (2.3 ± 0.3 versus 3.0 ± 0.2), when compared to the controls subjects. Sizes of the subdural haematoma world larger among patients underwater in administration, who also reported higher rates of mortality (55%), in comparison to haematoma patients without anticoagulation therapy (29%)⁸. Recurrent haematoma was found among patients after 25 days, who were under antiplatelet therapy that comprised of heparin, clopidogrel and aspirin⁹.  Preoperative mortality rates for around 0.5% were much less than other studies with that focused on subdural haematoma patients under warfarin medication. No associated comorbidities of heart failure, pulmonary embolism, or aortic valve disease were found to create any impact on clinical outcome of these patients. Impacts of preoperative anticoagulation were also evaluated on the outcomes of subdural haematoma patients in another study that focused on utilisation of the Barthel Index (BI), Rankin Scale (mRS) score and quality of life (QoL) scales. 21 patients reported a BI scor <100, while 53 had mRS score >1⁶. High rates of in-hospital mortality (42.3%) also found in another prospective cohort study that had taken into account patients treated with warfarin, following acute intracranial hemorrhage⁷. Rankin scale measures for degrees of disability of dependents were found to be approximately 5 for these patients under warfarin medication.

Several studies evaluated impacts of anticoagulation resumption on acute subdural hemorrhage. A retrospective study was conducted among 140 patients under low dose medication of acetylsalicylic acid after burr-hole drainage of subdural haematoma. No significant associations were found between the low dose of the anticoagulation resumption and recurrence of subdural haematoma among the patients (95% CI, 1.001-1.022; P =.06)¹⁰.  Optimal timings of resumption of warfarin after subdural haemorrhage were investigated by another study that calculated the cardiac indications for anticoagulation or previous stroke with the help of Cox model. While 177 patients under warfarin-induced subdural haemorrhage were found to survive the first week, 59 patients received the medication after 5.6 median weeks (IQR 2.6 –17). While warfarin resumption was found to produce recurrent haemorrhage and had a hazard ratio 5.6, when compared to that of 0.11 hazard ratio for stroke. Optimal water in reception time was an estimated 10 to 30 weeks, which was found to increase risks of subdural haemorrhage and ischemic stroke¹¹. In another retrospective cohort study 71 patients were found to report major haemorrhage symptoms and 110 of them experience symptoms of minor haemorrhage. Thromboembolism was also found among eight patients. Kinds of antithrombotic agents did not create any significant impact on haemorrhage frequency when compared to patients without the history of any anticoagulant medication. Risks of rebleeding were also found among patients who had resumed the anticoagulation therapy, after the operation for subdural haematoma OR 0.06; 95% CI 0.02–0.2; p < 0.01). Early resumption of antithrombotic agent within 3 days, post operation was considered safe for subdural haematoma patients¹².

Conclusion

Significantly high subdural haematoma associated risks are observed among patients who are underwater in medication in comparison to other antiplatelets. Intracellular haemorrhage exists in less frequency in combination with the use of other oral anticoagulant. Upon comparison with other forms of antiplatelet therapy, warfarin has been found to increase risks of subdural haematoma by three times. This shows consistency with previous findings of a systematic review that included 9 trials focusing on antiplatelet therapy, in that was conducted among 11000 participants¹³. Upon comparison of warfarin with direct oral thrombin inhibitors such as dabigatran, subdural haematoma was found at an increased risk of 80% with warfarin medication. Similarities for also found with another study that demonstrated risks of subdural haematoma with antiplatelet and warfarin therapy (OR, 3.0; 95% CI, 1.5, 6.1), compared to factor Xa inhibitors (OR, 2.9; 95% CI, 2.1, 4.1)¹⁴. Fewer evidences exist in cases of atrial fibrillation or myocardial infarction, whether INR elevation in absence of warfarin therapy, will indicate traumatic coagulopathy. There exist a range of outcomes with preoperative use of warfarin, when compared to without its use. Warfarin has been found to result in deterioration of the functional and clinical outcome of patience, than other anticoagulants¹⁵.

No functional improvements were also seen among the patients, despite enhancement of the neurological function. Surgical evaluation plays an essential role in elderly patients under anticoagulation therapy, who have undergone burr-hole drainage for subdural haematoma. Apart from thromboembolism and atrial fibrillation, falls are also associated with increased rates of injury among patients. Older people under anticoagulation therapy have been found to demonstrate increase rates of mortality. This identifies the potential for increasing incidence of intracranial haemorrhage and subdural haematoma among such people. Warfarin use an abnormal INR, when compared to other anticoagulants have independently predicted increased risks of ICH in cases of ground level falls, among patients¹⁶. New model anticoagulants such as, factor Xa inhibitor has been found to lack reversal agents on comparison to warfarin¹⁷.

Emerging evidence exists for reduced risks of subdural haemorrhage, with the use of new oral anticoagulants, in place of warfarin. Taking into consideration elderly patients with more incidence rates of chronic subdural haematoma, novel oral anticoagulant therapy should be considered as the mainstay treatment. Lower risks of intracranial haemorrhage have also been observed during NOAC medication, when compared to warfarin¹⁸.

Greater emphasis must also be put to patient education. Efforts must be taken by nursing professionals to create awareness among patients about the risk factors and lifestyle modifications that are associated with effects of anticoagulant. Potential risks and benefits of anticoagulant therapy must also be discussed with the patients¹⁸.

Lack of clarity exists regarding the efficacy and safety of resuming warfarin treatment among adult patients, following an intracranial haemorrhage or subdural haematoma. Further randomised control trials should be conducted for data mining risks of recurrent intracranial hemorrhage after resumption of anticoagulation therapy. New oral anticoagulants have been identified safe, with lower incidence of intracranial haemorrhage and can be restarted, whenever necessary²⁰. However, several challenges exist due to lack of optimal reversing agent. More trials should be conducted for developing reversal agents that are normal and safe for new generation oral anticoagulants.

The systematic review has several limitations in terms of careful interpretation of data, which prevents for the recommendations for patient care. However, quality of the review has not been compromised, since data has been collected from heterogeneous patient groups, regardless of their ethnicity and background, from prospective and retrospective cohort studies. The studies provide high quality evidence for the same. One major limitation can be associated with the fact that the observational studies included non-binding methods, which might have added to bias in the results. Studies published over a long period have also been used for data collection. Reporting bias is restricted, since case reports are not included in the review. It might be effective to conduct prospective trials, for drawing a firm conclusion¹⁴.

Conclusion

Warfarin administration has been associated with development of high intracranial pressure that subsequently leads to subdural haematoma, among adults under anticoagulant therapy. Major findings of the study suggest that administration of warfarin medication results in a deterioration of clinical and functional outcomes, upon comparison to other anticoagulants and also elevates the mortality rate. Thus, it can be concluded that resumption of anticoagulants as early as 5 days, post operation is considered safe for patients, having suffered intracranial haemorrhage, more commonly subdural haematoma. Future research must be targeted to reduced incidence of mortality and morbidity in elderly patients and anticoagulation therapy. This calls for the need of an effective collaboration between emergency department personnel, transfusion medicine, hematology, neurosurgery services, and critical care specialists.

References

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