Resumption of anticoagulation therapy after spontaneous intracerebral hemorrhage with patients mechanical heart valves
Introduction
Anticoagulation therapy is recommended in all patients with mechanical valvular replacement due to the significant associated risks of thromboembolism and valve dysfunction (1). Anticoagulation management is dependent on thrombogenicity, the site of valve replacement, and the associated risk factors of the valve (2). Bleeding events related to long-term oral anticoagulant therapy, for coagulation was not monitored during warfarin administration, the incidence of intracerebral hemorrhage (nearly 0.3–0.7% per year), are the most common complications in patients with mechanical valves (3). However, the temporary cessation of anticoagulant therapy may lead to the risk of valve thrombosis and stuck valve. Therefore, balancing the risk of recurrent cerebral hemorrhage and thromboembolism is crucial for such patients (4,5). Unfortunately, currently there is no consensus or guideline on when to restart anticoagulation therapy after cerebral hemorrhage in patients with mechanical valves.
This retrospective study analyzed the diagnosis, treatment, and prognosis of restarting anticoagulation therapy in patients with mechanical heart valves after spontaneous cerebral hemorrhage. This is the first cohort study of resumption of anticoagulation therapy reported from China.
We present the following article in accordance with the STROBE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-21-6848/rc).
Methods
The electronic medical records of 40 patients with mechanical valves who experienced spontaneous cerebral hemorrhage and were admitted to the Second Affiliated Hospital of Zhejiang University School of Medicine between 2013 to 2018 were retrospectively analyzed. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics committee of the Second Affiliated Hospital of Zhejiang University School of Medicine (No. 2020-318). Individual consent for this retrospective analysis was waived. A total of 4 patients died during hospitalization and anticoagulation therapy was resumed in 36 patients to prevent mechanical valve thromboembolism. A head computed tomography (CT) examination and surgery was performed on the first day after bleeding to confirm that the bleeding was stable or that the hematoma had been removed. Resumption of anticoagulation therapy was at the discretion of the neurosurgical doctor and was dose-adjusted based on the international normalized ratio (INR) standard.
Patients were divided into 2 groups based on whether anticoagulation therapy was resumed within 3 days after cerebral hemorrhage or more than 3 days after hemorrhage. All patients were followed-up for 12 months or more.
Patient data, including age, gender, type of mechanical heart valve, replacement time, replacement site, underlying disease, anticoagulant drugs at admission, type of cerebral hemorrhage, treatment mode, time without anticoagulant, length of hospital stay, and mortality, were collated and reviewed.
Statistical analysis
The SPSS25 software was used for statistical analysis and the analysis of variance (ANOVA) single factor test was used to compare 2 groups. A P value <0.05 was considered statistically significant.
Results
General information
During the 5-year study timeframe, there were 40 patients with mechanical heart valve replacement who experienced spontaneous cerebral hemorrhage. All patients were receiving oral warfarin anticoagulant therapy prior to admission (1.5–3.25 mg). Upon admission, patients were immediately administered fresh frozen plasma and vitamin K1 to eliminate the effect of anticoagulation. A total of 16 patients underwent surgical intervention and 24 patients were managed with conservative treatment. Unfortunately, there were 4 in-hospital deaths due to deterioration of the cerebral hemorrhage and thus, anticoagulant therapy could not be restarted in these patients.
The clinical characteristics of the remaining 36 patients are shown in Table 1. There was no significant difference between male and female patients. The age of onset ranged from 50–70 years old. Cerebral hemorrhage occurred within 10 years of valve replacement in 30 patients and after 20 years in a 29-year-old young man. A total of 16 patients presented with more than 2 chronic diseases before admission, predominantly hypertension, atrial fibrillation, and diabetes. No basic chronic disease was noted in 9 patients.
Table 1
| Variables | Overall (n=36) | Restart anticoagulation within 3 days (n=18) | Restart anticoagulation after more than 3 days (n=18) | P value |
|---|---|---|---|---|
| Age (years), median [IQR] | 60 [51–67] | 61 [51–68] | 61 [52–63] | 0.614 |
| Female, n [%] | 18 [50] | 10 [56] | 8 [44] | 0.519 |
| Duration from valve replacement to ICH onset (years), median [IQR] | 5 [2–9] | 7 [3–10] | 3 [2–9] | 0.338 |
| Valve repair, n [%] | 0.695 | |||
| Aortic | 10 [28] | 5 [28] | 5 [28] | |
| Mitral | 17 [47] | 9 [50] | 8 [44] | |
| Both | 9 [25] | 4 [22] | 5 [28] | |
| Comorbidities, n [%] | ||||
| Hypertension | 17 [47] | 8 [44] | 9 [50] | 0.747 |
| Atrial fibrillation | 14 [39] | 6 [33] | 8 [44] | 0.508 |
| Diabetes mellitus | 7 [19] | 3 [17] | 4 [22] | 0.684 |
| Other diseases* | 14 [39] | 9 [50] | 5 [28] | 0.181 |
| Pre-admission antithrombotic, n [%] | 1.000 | |||
| Warfarin | 32 [89] | 16 [89] | 16 [89] | |
| Warfarin plus antiplatelet agent | 4 [11] | 2 [11] | 2 [11] | |
| Location, n [%] | 0.261 | |||
| Parenchymal hemorrhage | 27 [75] | 12 [67] | 15 [83] | |
| Subdural hematoma | 9 [25] | 6 [33] | 3 [17] | |
| Operation, n [%] | 14 [39] | 11 [61] | 3 [17] | 0.005 |
*, coronary heart disease, cerebral infarction, pacing surgery. ICH, intracerebral hemorrhage; IQR, interquartile range.
Resumption of anticoagulation
There were 18 patients who restarted anticoagulation therapy within 3 days after cerebral hemorrhage and 18 patients whose anticoagulant therapy was resumed more than 3 days after hemorrhage. There were no significant differences in gender, age, valvular position, basic disease, type of cerebral hemorrhage, nor anticoagulation intensity before admission between the 2 groups (Table 1). However, patients who underwent surgical intervention resumed anticoagulation therapy earlier than patients who received conservative treatment (Figure 1).
Prognosis
Table 2 lists the basic characteristics of the patients and the anticoagulant treatment during hospitalization. Patients were followed-up for 12 months or more after discharge. A total of 30 patients survived and 6 died. There was no significant difference in valve replacement site, basic disease, bleeding type, nor interrupted anticoagulation time between patients who survived and those who died (Table 2). The length of hospital stay in the deceased group of patients was significantly longer and that in patients who survived (Figure 2). Of the 6 deceased patients, including 5 males and 1 female, all died due to cerebral parenchymal hemorrhage. Two cases received conservative treatment and 4 cases received surgical treatment. The onset age of deceased patients was higher compared to patients who survived (66 and 59 years, respectively). The interval time between valve replacement and cerebral hemorrhage was shorter (3 vs. 6 years) and the anticoagulation intensity before admission was higher (combined anticoagulation was 33% vs. 7%) in deceased patients compared to patients who survived. Of all the patients followed up, 14 received surgical treatment, 86% (12/14) of whom received surgical intervention within 48 h after admission. Among the 22 cases that were treated conservatively, the majority (20/22, 91%) presented with cerebral parenchymal hemorrhage. No clinically significant thromboembolism, bleeding recurrence, nor other malignant events were found after the resumption of anticoagulation therapy during hospitalization.
Table 2
| Variables | Survival group (n=30) | Deceased group (n=6) | P value |
|---|---|---|---|
| Age (years), median [IQR] | 59 [49–66] | 66 [62–68] | 0.114 |
| Male, n [%] | 13 [43] | 5 [83] | 0.077 |
| Age of valve replacement (years), median [IQR] | 6 [2–10] | 3 [2–3] | 0.122 |
| Valve repair, n [%] | 0.726 | ||
| Aortic | 8 [27] | 2 [33] | |
| Mitral | 14 [47] | 3 [50] | |
| Both | 8 [27] | 1 [17] | |
| Comorbidities, n [%] | |||
| Hypertension | 14 [47] | 3 [50] | 0.885 |
| Atrial fibrillation | 12 [40] | 2 [33] | 0.768 |
| Diabetes mellitus | 6 [20] | 1 [17] | 0.856 |
| Other disease* | 12 [40] | 2 [33] | 0.768 |
| Pre-admission antithrombotic, n [%] | 0.060 | ||
| Warfarin | 28 [93] | 4 [67] | |
| Wafarin plus antiplatelet agent | 2 [7] | 2 [33] | |
| Location, n [%] | 0.128 | ||
| Parenchymal hemorrhage | 21 [70] | 6 [100] | |
| Subdural hematoma | 9 [30] | 0 [0] | |
| Operation, n [%] | 10 [33] | 4 [67] | 0.134 |
| Duration of withholding anticoagulation (d), median [IQR] | 5 [1–13] | 6 [3–15] | 0.678 |
| Length of stay in hospital (d), median [IQR] | 12 [8–16] | 23 [18–44] | 0.001 |
*, coronary heart disease, cerebral infarction, pacing surgery. ICH, intracerebral hemorrhage; IQR, interquartile range.
Discussion
This study retrospectively analyzed the treatment of 40 patients with a history of mechanical heart valve replacement who experienced spontaneous cerebral hemorrhage. Following hemorrhage, the clinical management of such patients must balance the risk of delayed thromboembolism associated with anticoagulation reversal and the risk of hematoma dilation or rebleeding associated with recommencement of anticoagulation. The risk of spontaneous intracranial hemorrhage increases with prolonged oral warfarin treatment time and anticoagulation strength, and indeed, oral warfarin anticoagulation has been associated with a mortality rate of nearly 50% (3). In this current study, 25% (10/40) of patients with spontaneous cerebral hemorrhage died, 10% (4/40) died during hospitalization, and 15% (6/40) died from sepsis after discharge. In this study cohort, 78% (31/40) of intracranial hemorrhage occurred in the intracerebral internal parenchymal, which has been documented to be the most common site (3). The average age of onset was 60 years old, and there was no difference in the incidence of male and female patients. Spontaneous cerebral hemorrhage occurred about 5 years after anticoagulation treatment following valve replacement. The majority of follow-up patients were managed with low levels of warfarin anticoagulation therapy (1.5–3 mg/day) and the INR was maintained (1.7–2.2). There was no obvious increase in the incidence of bleeding events, nor thromboembolisms, nor any other malignant events.
Wijdicks and colleagues (6) demonstrated that interruption of anticoagulants for 1–2 weeks did not increase the incidence of thromboembolism complications nor recurrence during hospitalization. This concurs with our current data showing that interruption of anticoagulation for an average of 6 days was not associated with increased risk of thromboembolism, nor similar events or complications. Anticoagulant therapy was restarted within 1 week in 22 patients (61%), with no bleeding events reported. Other studies have also suggested that early initiation of anticoagulation was associated with a very low risk of increased bleeding (7,8). For patients with artificial valves, heparin anticoagulation can be resumed within 3 days at the earliest, and can be converted to oral anticoagulation in the form of warfarin within 7 days, without the risk of hematoma expansion due to increased bleeding. The timing of restarting anticoagulation therapy should be evaluated individually based on the specific risk factors associated with the valve and the potential causes of bleeding. The risk factors for systemic bleeds, such as previous extracranial bleeds (for example, in the gastrointestinal tract) and other risk factors, including liver and kidney disease, hypertension, and cancer, should also be considered. In this study cohort, there were 36 patients who restarted anticoagulation after hemorrhage, including 17 patients with mitral valve replacement, 10 patients with aortic valve replacement, and 9 patients with mitral valve combined with aortic valve replacement. Among them, there was no difference in the time without anticoagulation therapy, and the location and number of valve replacement did not affect the clinical decision regarding when to restart anticoagulation therapy. Most patients in the study cohort presented with existing comorbidities including hypertension (47%), atrial fibrillation (39%), and diabetes (19%). Recurrent bleeding that occurs before the recommencement of anticoagulation therapy may result from inadequate initial blood coagulation. Re-bleeding of the initial hematoma results in growth of the hematoma. The low-density areas, observed on computed tomography (CT) scans, that surround the cerebral hematoma are rich in thrombin, serum inflammatory proteins, and enzymes, and warfarin may prolong the retention effect, resulting in hematoma expansion. Therefore, the decision to resume antithrombotic therapy for the patients depends on the risk of subsequent thromboembolism and recurrent intracranial hemorrhage, and the patient’s overall disease status. To date, only a few retrospective case reports have been documented (9-11) and there is currently no consensus on when to resume oral anticoagulation therapy after an intracerebral hemorrhage.
Chandra et al. (7). suggested that it is safe to stop anticoagulant drugs for 7–14 days after the occurrence of an intracerebral hemorrhage, and then restart oral anticoagulant therapy. In the absence of guidelines and more evidence-based medicine, decisions are often made based on past experience or individual considerations. Based on our experience, early surgical hemostasis, postoperative control of blood pressure, and maintenance low INR (1.7–2.0) might be appropriate.
Conclusions
Hemostatic measures might be an important factor to think about resumption of anticoagulation. While the patient’s individual risk factors should be considered, it appears safe to halt anticoagulation therapy for 3 to 7 days after hemorrhage, with administration of low molecular heparin as a bridge treatment within 3 days and warfarin anticoagulant therapy within 1 week. It is also recommended that multidisciplinary teams (including cardiovascular surgery, hematology, and neurosurgery) be invited to assist in making effective and appropriate management decisions for the relaunch of anticoagulation management in these cases.
Study limitations
There were some limitations to this study. This was a single-center retrospective study, involving only 40 patients, and the decision for anticoagulation reversal was dependent on the experience of the attending neurosurgical doctor. Further multi-centered studies are warranted to confirm verify these results and to evaluate the risk of bleeding and thrombosis in such patients.
Acknowledgments
Funding: None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-21-6848/rc
Data Sharing Statement: Available at https://atm.amegroups.com/article/view/10.21037/atm-21-6848/dss
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-21-6848/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics committee of the Second Affiliated Hospital of Zhejiang University School of medicine (No. 2020-318). Individual consent for this retrospective analysis was waived.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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(English Language Editor: J. Teoh)
