Acidente vascular cerebral e ataques isquêmicos transitórios relacionados à interrupção de antiplaquetários ou varfarina

Arq Neuropsiquiatr anp Arquivos de Neuro-Psiquiatria Arq. Neuro-Psiquiatr. 0004-282X 1678-4227 Academia Brasileira de Neurologia - ABNEURO RESUMO Pacientes em terapia anticoagulante ou antiagregante plaquetária frequentemente são solicitados a descontinuar essas medicações antes e durante procedimentos cirúrgicos ou invasivos. Se o paciente interromper tratamento sem supervisão médica, poderá aumentar de risco de acidente vascular cerebral (AVC). Objetivo Identificar prevalência de AVC isquêmico e ataque isquêmico transitório (AIT) associados à descontinuação de terapia antiplaquetária ou coumarínicos em pacientes internados em hospital especializado em atendimento neurológico no Brasil. Métodos Estudo transversal, retrospectivo de três anos, descritivo dos pacientes hospitalizados por AVC. A revisão de relatórios médicos determinou características do AVC, fatores de risco, motivos e tempo de interrupção medicamentosa. Resultados Em três anos, foram internados 360 pacientes por AVC ou AIT; destes, 27 interromperam temporariamente terapia antiplaquetária ou coumarínicos relacionando ao evento (81% acidente vascular cerebral isquêmico, 19% AIT). A prevalência foi de 7,5%. O tempo médio entre interrupção antiplaquetária e evento foi cinco dias, com 62% deles ocorrendo até sete dias após suspensão medicamentosa. Para coumarínicos, o tempo médio foi 10,4 dias (d.p.= 5,7), em 67% dos casos o tempo entre a descontinuação medicamentosa e o evento foi 7-14 dias. O motivo mais frequente para suspensão do medicamento foi negligência do paciente (37%), seguido por cirurgia planejada ou exame invasivo (26%) e efeitos colaterais, incluindo hemorragia (18,5%). Conclusão Suspensão de terapia de antiplaquetários ou coumarínicos tem relação temporal com ocorrência de AVC e de AIT. Esses eventos são passíveis de serem evitados, sendo imprescindível que profissionais de saúde convençam seus pacientes das consequências graves da retirada do medicamento. Patients taking antithrombotic therapy for vascular risk reduction are often asked to discontinue these drugs before and during surgical or invasive procedures1. In high risk patients, bridging therapy may be indicated2. The initial treatment should be resumed as soon as possible after the surgery or invasive procedure1. However, in some cases the treatment is stopped at the patient’s will, without medical supervision, because of adverse events, drug interactions, dementia or neglect2. In this study we aimed to identify, among stroke patients, the prevalence of cases in which such events had a temporal association with discontinuation of antiplatelet or anticoagulant therapy. The factors that led to drug interruption and the interval between discontinuation and stroke were investigated in the study. METHODS This was a cross-sectional, retrospective, descriptive study of a sample of acute stroke patients hospitalized in a neurological hospital in Brazil, between 2007 and 2009. We included patients with a diagnosis of ischemic stroke or transient ischemic attack (TIA) whose medical history indicated that interruption of antiplatelet or oral anticoagulant agents was time-related to the occurrence of stroke. Hemorrhagic strokes were not included. Demographic and clinical data were collected from the medical records (Table 1). For antithrombotic therapy, we investigated the class and dosage of anticoagulant or antiplatelet, reason for treatment discontinuation and time interval between drug interruption and the occurrence of the ischemic event. Table 1 Demographic and clinical features. Age in years 68 ± 12.7 Sex % Male 48 Female 52 Vascular risk factors % Arterial hypertension 88.8 Hypercholesterolemia 62.9 Atherosclerotic carotid disease 62.9 Previous stroke or transient ischemic attack 48.1 Positive cardiovascular history 48.1 Atrial fibrillation 33.3 Smoking 29.6 Diabetes mellitus 18.5 Patent foramen ovale 11.1 Therapy interrupted % Aspirin (*) 55.5 Clopidogrel 18.5 Warfarin 26 *There was one patient on concomitant aspirin and warfarin treatment. Arterial hypertension was defined as arterial blood pressure greater than 140 / 90 mmHg. Diabetes mellitus was defined as a fasting glucose serum level greater than 126 mg/dL. Hypercholesterolemia was defined as a total fasting cholesterol serum level of greater than 200 mg/dL. Smoking was classified as present or absent on admission to hospital. Positive cardiovascular history was defined as the presence of one or more of the following in the medical history: acute myocardial infarct, unstable angina, coronary angioplasty, myocardial revascularization surgery and other embolic cardiopathies, such as Chagas disease, dilated myocardiopathy and valve prosthesis. A descriptive statistical analysis was carried out, data are expressed as mean ± standard deviation and prevalence, using Microsoft® Excel® software. RESULTS In the study period, there were 370 admissions due to stroke or TIA. We identified 27 cases (7.5%) with a present history of antiplatelet or anticoagulant drug interruption that was time-related to the event (81% ischemic strokes and 19% TIAs). Stroke clinical data are shown in Table 2. Patients were taking antithrombotic drugs to reduce cardiovascular risk (54.8%) or for stroke prevention (48.2%). Table 3 summarizes the patients’ reasons for discontinuing therapy. Table 2 Stroke classification. BAMFORD clinical classification % Partial anterior circulation stroke 55.0 Lacunar stroke 30.0 Posterior circulation stroke 15.0 TOAST etiologic classification % Cardioembolism 33.0 Large artery atherosclerosis 26.0 Small-vessel occlusion 11.0 Undetermined etiology* 30.0 *All had two or more causes identified. Table 3 Reasons for discontinuation of antithrombotic therapy. Reason % Patient’s negligence 37.0 Planned surgery or invasive examination 26.0 Side effects (including hemorrhage) 18.5 Not assessed 11.1 Other* 7.4 *Other includes one patient with clopidogrel interruption for anticoagulation bridging therapy and one patient on dual antiplatelet therapy, in whom one drug was stopped three months after coronary angioplasty and stenting. The median time between interruption of antiplatelet therapy (aspirin and clopidogrel) and an ischemic event was five days (range = 3 to 120). In 62% of the patients, stroke or TIA occurred within seven days of interruption of therapy. For vitamin K antagonists, the mean time between interruption of therapy and an ischemic event was 10.4 days ± 5.7 (range = 2 to 15) and, in 67% of the patients, the time between drug discontinuation and an ischemic event ranged from 7–14 days. By discharge, 41% had resumed to their original treatment, 38% were changed to dual antiplatelet therapy, 31% changed antiplatelet agent and 31% changed to an oral anticoagulant. DISCUSSION Why is treatment sometimes interrupted? In the present study, we observed that there was a considerable proportion (7.5%) of patients in whom stroke was not only time-related to warfarin interruption but also to the withdrawal of antiplatelet drugs. In these patients, the antithrombotic drug withdrawal may have contributed to the event. Aspirin interruption has already been shown to be a risk factor for the occurrence of acute myocardial infarction3 and stroke2. A large study on low-dose acetylsalicylic acid interruption revealed that, in the stroke group, nonadherence was the main cause of acetylsalicylic acid discontinuation, followed by treatment change4. Maulaz et al.2 showed, in a case-control study of aspirin users, that drug interruption had an odds ratio of 3.4% for ischemic cerebrovascular events. The reasons they identified for the interruption of therapy (planned invasive procedures, side effects including bleeding and nonadherence to the treatment) were present in similar proportions to those described in the present study. Our findings revealed that patient negligence was the main reason for stopping the therapy. Failure to adhere to the therapy may be due to inadequate medical guidance on the importance of treatment, but high drug costs may also explain some cases. Treatment adherence must be reinforced with patients4, particularly the elderly and those on polypharmacy—groups susceptible to adverse events—in whom treatment interruption without medical guidance is more likely5. The most important reason for discontinuing antiplatelet or anticoagulant therapy before invasive procedures is the risk of hemorrhage. A recent survey on a population in whom 62% of the interviewed were on antithrombotic therapy, found that 10% of the participants had stopped taking their medications, either anticoagulants (20%) or antiplatelets (9%), within 60 days prior to a medical intervention. The study also found antiplatelet drugs to be discontinued mainly for colonoscopies and orthopedic surgeries, and anticoagulant withdrawal mostly for orthopedic and vascular surgeries6. When a patient on an antithrombotic drug requires interruption for an invasive procedure, we should evaluate at least three points: 1) hemorrhagic risk of surgery; 2) patient vascular risk (ischemia or thrombosis); and 3) renal function in patients taking non-vitamin K direct anticoagulants7,8. In high-risk patients taking a vitamin K antagonist, subcutaneous low-molecular-weight heparin therapy should be considered9. A literature review by Ayoub et al.10, from trials of heparin or low-molecular weight heparin bridging in atrial fibrillation patients, who required temporary vitamin K antagonist interruption for surgery or procedure, showed increased risk of periprocedural hemorrhage, but no difference in mortality compared with patients who had not received bridging therapy. Does interruption of anticoagulant and antiplatelet drugs have a prothrombotic effect? Submission of a patient with prothrombotic conditions to a surgical procedure, which in itself promotes a hypercoagulable state1, could increase the risk of an ischemic event. After interruption of aspirin or clopidogrel, a stroke or TIA may be explained not only by the new platelets pool but also by a prothrombotic rebound effect2,11. After discontinuation of clopidogrel, normal platelet function returns after seven days12. However, an impedance-induced platelet aggregation sequential study on whole blood taken from 28 coronary stented patients, in whom clopidogrel was interrupted abruptly after a year of continuous use, found platelet hyperreactivity in more than half of the patients from week two to week six, thus suggesting patients who withdrew from clopidogrel to be at an even greater risk11. In the present study, the majority (62%) of the events occurred within seven days of antiplatelet interruption, corroborating the theory of a prothrombotic effect after interruption of this therapy. A 2011 study on the interruption of low-dose antiplatelet therapy for the prevention of ischemic stroke or myocardial infarction in a cohort of 39,512 selected patients followed for an average of 3.42 years, found that interruption of acetylsalicylic acid lead to a 40% increase in the risk of ischemic stroke or TIA. The risk was higher among the recent discontinuers (1–15 days)4. Another cohort study done using a five-year Danish stroke registry correlated antiplatelet therapy discontinuation with increased risk of ischemic stroke13. Increased prothrombotic activity also occurred after warfarin interruption, resulting in increased thrombin production and platelet activation14. A more recent study on the risk of ischemic stroke in high risk atrial fibrillation patients 65 years old or older, with at least one additional risk factor for ischemic stroke, in whom warfarin was discontinued for surgical procedures, showed a higher rate of ischemic stroke in the warfarin-discontinued group (1.1% of 265 versus 0.4% of 71,355), a population attributable risk of 23.1%15. Another study on 27,000 nonvalvular atrial fibrillation patients found that interruptions of warfarin for 45 days or longer, significantly increased the chance of a cerebrovascular ischemic event or a TIA16. Study pitfalls This study has a number of limitations because of the absence of a control group (patients who discontinued the use of medications and did not have stroke or TIA). However, the objective of this analysis was not to compare our series with a control group but to point out that the risk of ischemic events in patients who interrupt antiplatelet or vitamin K antagonist therapy is real and should not be overlooked. Patients taking non-vitamin K antagonist direct anticoagulants were not included in this study because the drugs were not used in Brazil by the time of data collection. In conclusion, based on our results, we recommend that clinicians should be aware of antithrombotic therapy interruption before a stroke or TIA and verify any possible relationship to the event. Furthermore, patients should be informed about risks of inadequate interruption of antiplatelet or anticoagulant drugs. In high vascular risk patients, heparin or low-molecular weight heparin bridging therapy may be considered, but should be balanced against the periprocedural hemorrhagic risk. References 1 1. Douketis JD, Johnson JA, Turpie AG. 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