Background
Stroke is a leading global burden worldwide and is currently the second and third most common cause of mortality and disability, respectively. According to the American Stroke Association, one in four stroke survivors will have a recurrent stroke. In Bangladesh, the prevalence of stroke is 11.39 per thousand population and two-third of it is ischemic stroke.1,2
A study in a hospital setting in Bangladesh screened 689 ischemic stroke patients and confirmed 156 of them having had cardio-embolic stroke which is 22.64% of the total. This data is comparable to the West reporting a range of 15%-30% of cardio-embolic stroke. The major risk factors of cardio-embolic strokes were hypertension (76.3%), atrial fibrillation (68.6%), followed by ischemic heart disease (39.2%) which was mainly manifested by a history of myocardial infarction. Only 14.7% of the total number of patients came with chronic rheumatic heart disease. Cardiac emboli arising from cardiac causes are usually large, often underdiagnosed, and cause massive strokes leading to high morbidity and mortality. To avoid further strokes it is important to identify cardio-embolic stroke to plan anticoagulant treatment initiation.1
While ischemic stroke is the result of a blockage in the blood vessel supplying the brain from fatty plaque or by circulating blood clot arising usually from cardiac causes, the hemorrhagic stroke happens when the blood vessels in the brain leak or get ruptured. The underlying causes for hemorrhagic stroke are hypertension, over treatment with anticoagulants, aneurysms, trauma, protein deposits that weaken the vessels, and a simultaneous result of ischemic stroke.3
A full evaluation to initially diagnose the type of stroke is mandatory before anticoagulation therapy is started because the older practice of starting anticoagulation therapy for all patients who had suffered acute ischemic stroke is less common now. Anticoagulation coverage for long-term prevention from recurrent stroke is clearly indicated for patients who have had ischemic stroke and are also presenting with atrial fibrillation (AF), as AF itself is a leading cause of cardioembolic stroke.4 There is debate on the timing of starting that therapy.5
The efficacy of the protocol is still unclear 6 but patients with recent strokes are routinely given anticoagulants for recurrent stroke prevention and improved neurological outcomes. The Cerebral Embolism Study Group enumerates a 12% risk of recurrent strokes in patients with embolic stroke if they remain untreated.7
The major concerns related to anticoagulant usage are:
1. The optimal time to initiate anticoagulant therapy post an acute stroke with AF.
2. The drugs of choice for valvular and non-valvular AF.
3. Anticoagulant therapy in chronic rheumatic heart disease (CRHD).
4. Resuming anticoagulant therapy after intracranial hemorrhage with AF.
This short review aims to shed light on the above-mentioned concerns based on the recently published articles.
Assessment of Patients Prior to Anticoagulation Therapy
Assessment of patients is of paramount importance before administering anticoagulants. CHA2DS2-VASc score is the cornerstone for patients with non-valvular AF who need anticoagulants.8
The score is a sum up of congestive cardiac failure, hypertension, age ≥ 75, diabetes, previous stroke, vascular disease, age 65-74 and sex category where each are assigned one point but stroke and age over 75 are assigned 2 points separately. A score of ≥2 in males and ≥3 in females, out of total 9 is indicative of anticoagulation therapy.8
Anticoagulation therapy needs monitoring to assess risks of bleeding. The HAS-BLED score is used to evaluate major bleeding risks in AF.9 The acronym stands for hypertension, abnormal renal and/or liver function, stroke, bleeding, labile INRs, elderly ≥ 65, drug therapy and/or alcohol intake where once again each of the risk factors are one point each with a maximum score of 9.10 HAS-BLED score does not exclude the use of anticoagulants in AFs but is used to predict bleeding risks and recommends monitoring of anticoagulants when a HAS‐BLED score is ≥3.9 Moreover, the severity of a stroke should be clinically measured by the National Institute of Health Stroke Scale (NIHSS) and radiologically by The Alberta Stroke Program Early CT score (ASPECT). A comprehensive decision based on these scoring systems can mostly be rational and beneficial to prevent not only further stroke but also anticoagulant-induced bleeding.
Timing of Initiating Direct Oral Anticoagulant Therapy Post-Acute Ischemic Stroke
To reduce further stroke and systemic embolism, direct oral anticoagulants (DOACs) are prescribed to patients who suffered acute ischemic stroke and are presenting with AF. Since there is high risk of recurrent ischemic stroke and intracranial hemorrhage during the first few days post an acute stroke, the guideline of the timing to initiate the DOAC therapy is varied.11
The New England Journal of Medicine published a study on 2013 participants in 15 countries to establish indications of “Early versus Later Anticoagulation for Stroke with Atrial Fibrillation”.11
1006 participants were selected for early anticoagulation where therapies would start within 48 hours after a minor or moderate stroke and six to seven days after major stroke. The remaining 1007 participants were assigned to the later anticoagulation therapy group where the standard recommended “1-3-6-12–day rule” was followed where anticoagulation was initiated 1, 3, 6, or 12 days after a transient ischemic attack (TIA), a minor, moderate, or severe stroke, respectively.11
The latter is the standard European guideline based on expert consensus, and the American Stroke Association recommend delaying initiating anticoagulation therapy even further beyond 14 days if there are high chances of hemorrhagic transformation.12
The criteria to select participants of the study followed neuroimaging confirmation that confirmed diagnosis of patients to have had a recent stroke with AF.11
The primary outcome events of the study were a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after initiation of therapy. The study included death related to vascular and non-vascular causes. Secondary outcomes assessed at 30 and 90 days were inclusive of- recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, vascular death, nonmajor bleeding, and death from any cause.11
A primary-outcome event occurred in 29 participants (2.9%) in the early-treatment group and in 41 participants (4.1%) in the later-treatment group. Death from non— vascular causes before 30 days occurred in 13 participants in the early-treatment group and in 11 participants in the later-treatment group. Recurrent ischemic stroke occurred in 14 participants (1.4%) in the early-treatment group and 25 participants (2.5%) in the later-treatment group by 30 days. Symptomatic intracranial hemorrhage occurred in 2 participants (0.2%) in both groups within 30 days.11
The overall incidence of a composite-outcome event at 90 days was 3.7% in the early-treatment group and 5.6% in the later-treatment treatment group. The cumulative rates of recurrent ischemic stroke at 90 days were 1.9% in the early-treatment group and 3.1% in the later-treatment group.11
The study justifies that there is a high level of probability that early DOAC treatment does not cause harm and a reasonable probability that it reduces the risks of a recurrent stroke or other ischemic event.12
The Drug of Choice for Valvular and Non-Valvular Atrial Fibrillation
A caveat remains regarding the selection of anticoagulants depending on the kind of AF the patients are suffering from. Although there are no specific guidelines, it is recommended that while choosing the anticoagulants, further screening of valvular or non-valvular AF must be in consideration. The non-vitamin K antagonist oral anticoagulants (NOACs) including the thrombin inhibitor dabigatran and the Factor Xa inhibitors- rivaroxaban, apixaban, and edoxaban are considered the gold standard for prophylactic therapy in patients having had stroke and presenting with non-valvular AF.4
Apixaban, edoxaban, and dabigatran cause fewer episodes of major bleeding and are strongly preventive in stroke recurrence and systemic embolism. They also do not require continuous monitoring as the vitamin K antagonists (VKAs) like warfarin. Confusions regarding the valvular and non-valvular AF arose when extensive trials done on NOACs did not include patients with mechanical mitral valves and patients having moderate to severe mitral stenosis which led to the guideline terming NOACs’ exclusivity to be used in non-valvular AF. This generalized term does not stand true because patients with AF additionally having aortic stenosis, aortic regurgitation, mitral regurgitation, bioprosthetic valves (both in aortic or mitral position) and mild mitral stenosis were included in trials comparing NOACs to VKAs.4,13
NOACs proved as safe and effective as VKAs in these patients just like it is in patients with non-valvular AFs. 13
Oral anticoagulants’ efficacy is monitored by the international normalized ratio (INR) testing which has a therapeutic range of 2.0-3.0. It is difficult to maintain this ratio with warfarin, and since warfarin increases the risk of bleeding, especially intracranial bleeding, frequent monitoring of INR is needed for patients receiving warfarin management. With NOACs, INR is more stable and requires less monitoring.
Ever since the invention of NOACs, multiple trials proved higher efficacy of NOACs to VKAs. Dabigatran, the direct thrombin inhibitor showed superior efficacy and lesser number of death than warfarin in the RE-LY study in patients with non-valvular AF. Rivaroxaban, a direct factor Xa inhibitor’s use for stroke and embolism prevention compared to warfarin in the ROCKET-AF trial proved noninferior efficacy to warfarin. Apixaban was compared to warfarin to achieve the INR between 2-3, and it showed lower rate of stroke, systemic embolism, hemorrhagic and ischemic stroke compared to warfarin in the ARISTOTLE trial. Edoxaban, the other factor Xa inhibitor was studied against warfarin in the ENGAGE AF-TIMI 48 trial and showed higher efficacy in high dose against stroke and embolism, but the low dose showed higher incidence of stroke compared to warfarin. NOACs are in general safer in reducing the occurrence of bleeding events, especially intracranial hemorrhage and if bleeding does happen, it is not as fatal as in warfarin. Since labile INR is a factor in the HAS-BLED score, maintaining the INR range is a defining factor of NOAC versus VKA management. NOACs have other added advantages like less drug-drug and drug-food interaction compared to VKA.
VKAs are the drug of choice in patients with renal impairment. NOACs are not recommended in patients with creatinine clearance of less than 30 mL/min. Previous studies did not consider use of NOACs in patients with mechanical heart valves and in patients having moderate to severe mitral stenosis, so VKAs are still the drugs of choice in these conditions. Finally, NOACs are expensive and patients who cannot afford them are kept on VKAs for preventive measures.14
Anticoagulant Therapy in Chronic Rheumatic Heart Disease (CRHD)
Before the era of NOAC, VKA oral anticoagulant mainly warfarin was the standard of care for both valvular and nonvalvular AF with rheumatic heart diseases. The discussion on drugs of choice with underlying valvular condition denotes the importance of selecting the right therapeutic. Rheumatic heart disease is a condition where heart valves are permanently damaged from untreated or under treated streptococcal infection.15 An echocardiographic evaluation is a must before any management either with NOAC or VKA is initiated to detect pre-existing valvular conditions. A randomized clinical trial showed that VKA given to patients having rheumatic heart disease with AF showed lower incidence of cardiovascular event and death than the NOAC rivaroxaban.4
Thus, the current guideline recommends use of VKAs in patients with rheumatic heart disease associated with AF.4
Resuming Anticoagulant Therapy after Intracranial Hemorrhage for AF
There is lack of evidence documenting the perfect time to resume oral anticoagulant (OAC) therapy after intracerebral hemorrhage (ICH) which can be a consequence of ischemic stroke.16
Nonvalvular AF is highly common among ICH survivors which overall increases the risk of ischemic stroke, recurrent ICH, and mortality.17 ICH itself is associated with mortality and stroke, and further anticoagulation-related ICH can cause devastating outcomes, hence all randomized trials usually exclude ICH survivors.16
However, the presence of AF in such cases are an indication to start anticoagulants to prevent ischemic stroke.17
Once again, the timing of resuming OAC therapies pose difficult clinical decision. The main balance is to identify the risk of patients developing recurrent ICH versus the risk of thromboembolism. It is also recommended to assess the modifiable risks like hypertension, anemia, renal dysfunction, diabetes, and heart failure.16
The majority of studies did not establish a conclusion regarding the safety of OAC resumption after an ICH in patients with nonvalvular AF.17
Some studies did find existing co-morbidities may increase the risk of ICH. For example, the site of initial ICH is important. Patients with Lobar ICH have a high risk of developing subsequent ICH compared to hemorrhage in deep cortical location. The other risk factors include- diabetes, Hepatitis C virus, hypertension, postoperative condition, and ethnicity (especially Asians are more prone to ICH). It is again reiterated that before resuming OAC after ICH, HAS-BLED score must be done to predict ICH after a first spontaneous ICH.16
In elderly persons (>55 years), lobar hemorrhage, sulcal hemorrhage, cortical microbleed, and deep bleeding are important factors for delaying anticoagulant therapy at least 4 weeks apart.
Only one study done on ICH survivors with nonvalvular AF showed that resuming anticoagulant therapy between 7 and 8 weeks after ICH reduces the risk of thrombotic events and recurrent ICH.17
Conclusion
All parameters enumerate a low likelihood that early anticoagulation therapy can be harmful by increasing the risk of hemorrhage,5 rather it prevents further stroke in atrial fibrillation. NOACs are preferably safe and as effective as VKA anticoagulants except in moderate to severe mitral stenosis and mechanical valve replacement. Resumption of anticoagulant after intracerebral hemorrhage is still a gray zone, it should be the clinicians’ judgement after assessing each case separately based on comorbidities, the severity of the stroke, site, and volume of hematoma.
Author of this article
- Dr. S K Jakaria Been Sayeed, MBBS, FCPS (Medicine), FCR (Harvard Medical School, USA), MRCP (Medicine-UK), FRCP (Medicine-Edinburgh), EULAR Fellow (Rheumatology), Academic Editor (PLOS ONE) Medicine & Rheumatology Specialist, National Institute of Neurosciences and Hospital, Dhaka.
- Dr. Abu Nayeem, Associate Professor, Clinical Neurology, National Institute of Neurosciences and Hospital, Dhaka.
References:
- Been Sayeed SKJ, Haque AM, Moniruzzaman Md, et al. Prevalence and Outcome of Cardio-Embolic Stroke Patients Admitted at Referral Neurology Hospital in Bangladesh. Cardiol Cardiovasc Med. 2022;06(05). doi:10.26502/fccm.92920286
- Mondal MBA, Hasan ATMH, Khan N, Mohammad QD. Prevalence and risk factors of stroke in Bangladesh: A nationwide population-based survey. eNeurologicalSci. 2022;28:100414. doi:10.1016/j.ensci.2022.100414
- Stroke – Symptoms and causes – Mayo Clinic. Accessed April 18, 2024. https://www.mayoclinic.org/diseases-conditions/stroke/symptoms-causes/syc-20350113
- Bang OY, Park KM, Jeong DS. Occurrence of Ischemic Stroke in Patients With Atrial Fibrillation Receiving Non-Vitamin K Oral Anticoagulants: Causes and Prevention Strategies. J Stroke. 2023;25(2):199-213. doi:10.5853/jos.2022.03552
- Anticoagulation Conundrum in Acute Ischemic Stroke with Atrial Fibrillation | New England Journal of Medicine. Accessed April 18, 2024. https://www.nejm.org/doi/10.1056/NEJMe2304801
- Fanaroff AC, Vora AN, Lopes RD. Non-vitamin K antagonist oral anticoagulants in patients with valvular heart disease. Eur Heart J Suppl J Eur Soc Cardiol. 2022;24(Suppl A):A19-A31. doi:10.1093/eurheartj/suab151
- Guidelines for the Early Management of Adults With Ischemic Stroke | Stroke. Accessed April 18, 2024. https://www.ahajournals.org/doi/full/10.1161/strokeaha.107.181486
- Ibdah R, Obeidat O, Khader Y, et al. Validation of CHA2DS2 VASc Score Predictability of Stroke and Systemic Embolization in a Middle Eastern Population with AF: The Jordan Atrial Fibrillation (JoFib) Study. Vasc Health Risk Manag. 2023;19:255-264. doi:10.2147/VHRM.S404575
- Zhu W, He W, Guo L, Wang X, Hong K. The HAS‐BLED Score for Predicting Major Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: A Systematic Review and Meta‐analysis. Clin Cardiol. 2015;38(9):555-561. doi:10.1002/clc.22435
- Bleeding risk: HAS-BLED bleeding risk score. GlobalRPH. Accessed April 18, 2024. https://globalrph.com/medcalcs/bleeding-risk-has-bled-bleeding-risk-score/
- Fischer Urs, Koga Masatoshi, Strbian Daniel, et al. Early versus Later Anticoagulation for Stroke with Atrial Fibrillation. N Engl J Med. 2023;388(26):2411-2421. doi:10.1056/NEJMoa2303048
- Slightly Better Outcomes Observed With Earlier Initiation of Direct Oral Anticoagulants in Atrial Fibrillation. Neurology live. Published May 25, 2023. Accessed April 18, 2024. https://www.neurologylive.com/view/slightly-better-outcomes-observed-earlier-initiation-direct-oral-anticoagulants-in-atrial-fibrillation
- Fanaroff AC, Vora AN, Lopes RD. Non-vitamin K antagonist oral anticoagulants in patients with valvular heart disease. Eur Heart J Suppl J Eur Soc Cardiol. 2022;24(Suppl A):A19-A31. doi:10.1093/eurheartj/suab151
- Guimarães PO, Kaatz S, Lopes RD. Practical and clinical considerations in assessing patients with atrial fibrillation for switching to non-vitamin K antagonist oral anticoagulants in primary care. Int J Gen Med. 2015;8:283-291. doi:10.2147/IJGM.S62760
- Rheumatic Heart Disease. Published March 12, 2024. Accessed April 18, 2024. https://www.hopkinsmedicine.org/health/conditions-and-diseases/rheumatic-heart-disease
- Anticoagulation Resumption After Intracerebral Hemorrhage | Current Atherosclerosis Reports. Accessed April 18, 2024. https://link.springer.com/article/10.1007/s11883-018-0733-y
- Hawkes MA, Rabinstein AA. Anticoagulation for atrial fibrillation after intracranial hemorrhage. Neurol Clin Pract. 2018;8(1):48-57. doi:10.1212/CPJ.0000000000000425