HomeCirculationVol. 128, No. 11Circulation Editors’ Picks Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCirculation Editors’ PicksMost Read Articles on the Topic of Stroke The Editors The Editors Search for more papers by this author Originally published10 Sep 2013https://doi.org/10.1161/CIRCULATIONAHA.113.005571Circulation. 2013;128:e162–e170Timing, Predictive Factors, and Prognostic Value of Cerebrovascular Events in a Large Cohort of Patients Undergoing Transcatheter Aortic Valve ImplantationSummary—Transcatheter aortic valve implantation has been associated with a higher rate of cerebrovascular events (CVEs) compared with medical treatment or surgical aortic valve replacement. This multicenter study evaluated in a large cohort of consecutive patients (n=1061) the timing, predictors, and clinical impact of CVEs after transcatheter aortic valve implantation. The incidence of 30-day CVEs was 5.1% (stroke, 4.2%), with about half of these events occurring immediately or within the first few hours after the procedure. The predictors of acute (≤24 hours) CVEs were mechanical factors such as further stretching of the valve prosthesis with balloon postdilation (odds ratio, 2.46; P=0.034) and valve dislodgment/embolization (odds ratio, 4.36; P=0.024), whereas subacute (1–30 days) CVEs were determined mainly by the occurrence of atrial arrhythmias (new-onset atrial fibrillation; odds ratio, 2.76; P=0.028). There were no differences in 30-day CVE rate between different types of valves (balloon expandable, self-expandable) or access routes (transfemoral, transapical). The rate of late (<30 days) CVEs was 3.3% (stroke, 2.1%) at a median follow-up of 12 months (3–23 months). The predictors of late CVEs were chronic atrial fibrillation (hazard ratio, 2.84; P=0.002), peripheral vascular disease (hazard ratio, 2.02; P=0.043), and prior cerebrovascular disease (hazard ratio, 2.04; P=0.047). The impact of CVEs on mortality was determined mainly by the severity of the event, and only the occurrence of major stroke was independently associated with an increased 30-day (hazard ratio, 7.43; P=0.001) and late cumulative (hazard ratio, 1.75; P=0.043) mortality. These results providing important insight into the pathophysiology and prognosis value of CVEs after transcatheter aortic valve implantation procedures should help to determine the most appropriate therapeutic measures to reduce the high incidence of CVEs associated with transcatheter aortic valve implantation.Conclusions—In a large cohort of patients undergoing transcatheter aortic valve implantation, the rates of acute and subacute CVEs were 2.7% and 2.4%, respectively. While balloon postdilation and valve dislodgment/embolization were the predictors of acute CVEs, new-onset atrial fibrillation determined a higher risk for subacute events. Late events were determined mainly by a history of chronic atrial fibrillation and peripheral and cerebrovascular disease. The occurrence of major stroke was associated with increased early and late mortality. These results provide important insights for the implementation of preventive measures for CVEs after transcatheter aortic valve implantation.1Stroke After Carotid Stenting and Endarterectomy in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)Summary—Stroke is a feared complication of carotid endarterectomy (CEA) and carotid stenting (CAS). The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) and European trials have shown that CAS is associated with a greater risk of stroke than CEA. CREST also showed that CEA was associated with a greater risk of myocardial infarction (MI) than CAS. The greater risk of MI numerically balanced the greater risk of stroke, so that the composite primary outcome (periprocedural stroke, MI, or death and ipsilateral stroke at up to 4 years) was similar for CEA and CAS. This result has invited criticism because of the differing directions of stroke and MI within the composite outcome. To understand further, we examined the strokes that occurred as a complication of the procedure. Stroke was still more common after CAS, but overall the risk of severe stroke was <1% and was similar for CEA and CAS. The delayed timing of some major strokes, particularly intracerebral hemorrhage that occurred a few days postoperatively, makes it plausible that these postoperative strokes are preventable, perhaps with careful attention to blood pressure control. Minor stroke occurred most commonly on the same day as CAS, which suggests that the technical aspects of the procedure could be improved to minimize stroke as a complication. Previously, we reported that MI, including biomarker-only MI, was associated with an increased risk in long-term mortality. Here we report that stroke, including minor stroke, was also associated with an increased risk in long-term mortality. Carotid intervention with CEA or CAS is safe. Periprocedural stroke incurred significant morbidity and mortality.Conclusions—Stroke, particularly severe stroke, was uncommon after carotid intervention in CREST, but stroke was associated with significant morbidity and was independently associated with a nearly 3-fold increased future mortality. The delayed timing of major and hemorrhagic stroke after revascularization suggests that these strokes may be preventable.2Targeting Mannose-Binding Lectin Confers Long-Lasting Protection With a Surprisingly Wide Therapeutic Window in Cerebral IschemiaSummary—Despite recent substantial progress in prevention and supportive care, stroke is still a leading cause of death and permanent disability worldwide. To date, thrombolysis with tissue plasminogen activator is the only available treatment and its narrow therapeutic window (3–4.5 hours) is one of the main obstacles to finding eligible patients. Thus, new approaches with a wider window of efficacy are needed. This study documents the pivotal role of mannose-binding lectin (MBL), a circulating protein that acts as the first step in activation of the lectin complement pathway in brain ischemic injury. The data show that MBL deposition on the ischemic endothelium represents a key pathogenetic event in brain damage. Importantly, strategies aimed at inhibiting MBL lead to neuroprotection with a time window of efficacy up to 24 to 30 hours postinjury, an extremely important factor in the attempt to translate experimental results into the clinical setting. Detailed analysis of the MBL gene in humans has revealed that a surprisingly high percentage of individuals (15% to 30% depending on the population considered) carries a genetic deficiency in MBL that leads to low circulating levels of MBL. Notably, this deficiency is associated with a better outcome after acute stroke in humans. Our data, providing a mechanistic insight into the role of MBL in brain ischemia and the demonstration that its inhibition is protective, strongly support the concept of MBL as a relevant therapeutic target in humans, one with a wide therapeutic window of application. Thus, we propose MBL as a novel therapeutic target for stroke.Conclusions—Our data show an important role for MBL in the pathogenesis of brain ischemic injury and provide a strong support to the concept that MBL inhibition may be a relevant therapeutic target in humans, one with a wide therapeutic window of application.3Cerebral Embolization During Transcatheter Aortic Valve Implantation: A Transcranial Doppler StudySummary—Neurological events are currently considered one of the most pressing concerns with transcatheter aortic valve implantation (TAVI). A nearly 4-fold risk of such events within 30 days after the procedure was observed for nonoperable patients undergoing TAVI compared with patients treated with optimal medical therapy in cohort B of the Placement of AoRtic TraNscathetER valves (PARTNER) trial, and similar results were found when TAVI was compared with surgical aortic valve replacement in the high-risk population of cohort A. Moreover, a high load of clinically silent embolic lesions was documented on postprocedural cerebral diffusion-weighted MRI, which has raised additional safety concerns. In the present study, serial transcranial Doppler monitoring was performed to elucidate the main source of procedural emboli. During TAVI, high-intensity transient signals were detected in all patients as a surrogate for microembolization. They predominantly occurred during manipulation of the calcified native valve while positioning and implanting the stent valves, with no differences between the transfemoral and the transapical approach and only a trend toward a higher amount of high-intensity transient signals for the self-expandable prosthesis. Despite the omnipresence of high-intensity transient signals, however, only 2 (2.4%) neurological complications occurred within 30 days, and there were no late neurological events. However, these findings corroborate the importance of periprocedural embolization during TAVI and reinforce current calls for an increased focus on this issue, especially when TAVI indications are broadened toward younger, lower-risk patients. Future research is essential to better determine the “real” neurological risk of the TAVI procedure and to thoroughly investigate the feasibility, safety, and efficacy of upcoming strategies to reduce the risk for cerebral embolization, eg, use of less traumatic devices, omission of preparatory valvuloplasty, carotid compression during valve manipulation, or use of active cerebral protection devices.Conclusions—Procedural high-intensity transient signals (HITS) were detected by transcranial Doppler in all patients. Although no difference was observed between the transfemoral and the transapical approach with the balloon-expandable ES stent valve, transfemoral TAVI with the self-expandable MCV prosthesis resulted in the greatest number of HITS, predominantly during implantation.4Association Between Major Perioperative Hemorrhage and Stroke or Q-Wave Myocardial InfarctionSummary—Perioperative stroke and myocardial infarction (MI) cause significant morbidity and mortality. Patients with vascular risk factors often continue to receive antiplatelet drugs during the perioperative period to reduce their risk of stroke and myocardial infarction. However, these drugs also increase the risk of surgical bleeding, and bleeding has been associated with a higher risk of ischemic complications in patients with acute coronary syndrome. Therefore, we investigated the association between perioperative hemorrhage and stroke or myocardial infarction in a large cohort of surgical patients prospectively assembled by the National Surgical Quality Improvement Program. In multivariable Cox proportional hazards analyses that controlled for vascular risk factors, type of surgery, and illness severity, we found that major perioperative hemorrhage was associated with higher risks of subsequent stroke (hazard ratio, 2.5; 95% confidence interval, 1.9–3.3), Q-wave myocardial infarction (hazard ratio, 2.7; 95% confidence interval, 2.1–3.4), and a composite of stroke or Q-wave myocardial infarction (hazard ratio, 2.6; 95% confidence interval, 2.2–3.1). These results underscore the importance of randomized clinical trials to define optimal strategies of perioperative antiplatelet use. In the meantime, clinical assessments of the risk of perioperative cardiac and neurological complications should account for surgical bleeding. Furthermore, our results highlight the importance of tightly coordinated multidisciplinary perioperative care of patients with vascular risk factors, especially in regard to perioperative antiplatelet treatment. Finally, clinicians should recognize that surgical patients with major hemorrhage may be more vulnerable to ischemic complications and may benefit from vigilant perioperative care and close observation to identify complications as soon as they arise.Conclusions—Major perioperative hemorrhage is associated with subsequent stroke and myocardial infarction in patients undergoing noncardiac, nonneurological surgery. This suggests the need for randomized trials to guide perioperative use of antiplatelet drugs, which affect the risk of both bleeding and vascular events.5The United States Registry for Fibromuscular Dysplasia: Results in the First 447 PatientsSummary—Fibromuscular dysplasia (FMD) is a nonatherosclerotic, noninflammatory vascular disease that primarily affects women in the prime of their life. There is an average delay of 5 years from the onset of symptoms until the diagnosis of FMD is made. FMD most commonly affects the renal, carotid, and vertebral arteries but may occur in virtually every artery of the body. Multivessel involvement is common. The most common clinical manifestations of FMD are hypertension, headaches, pulsatile tinnitus, and dizziness. However, 1 in 5 patients experience a dissection, and 17% have one or more aneurysms. A cerebrovascular event including transient ischemic attack, stroke, and/or amaurosis fugax occur in 1 of every 4 patients with FMD. The presence of a carotid bruit in a patient under 60 or an epigastric bruit in a patient with hypertension should alert the clinician to the possible diagnosis of FMD. Earlier diagnosis may prevent the consequences of poorly controlled hypertension, and allow for the identification of aneurysms and dissections and their appropriate treatment.Conclusions—In this registry, FMD occurred primarily in middle-aged women, although it presents across the lifespan. Cerebrovascular FMD occurred as frequently as renal FMD. Although a significant proportion of FMD patients may present with a serious vascular event, many present with nonspecific symptoms and a subsequent delay in diagnosis.6Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and a History of Stroke or Transient Ischemic AttackSummary—Patients with acute coronary syndromes and a history of prior stroke are at a high risk of ischemic and bleeding events and constitute a treatment challenge. Therefore, novel and more potent antithrombotic agents need to be evaluated with regard to the balance between efficacy and safety, particularly in the most vulnerable patients. Ticagrelor provides faster, greater, and more consistent platelet inhibition than clopidogrel. The PLATelet inhibition and patient Outcomes (PLATO) trial showed that ticagrelor was superior to clopidogrel in a broad population of patients with acute coronary syndromes for the prevention of cardiovascular death, myocardial infarction, or stroke but with an increase in overall major bleeding events not associated with coronary artery bypass surgery. Among the 18 624 patients randomized in the PLATO study, 1152 (6.2%) were reported as having a history of stroke or transient ischemic attack. These patients presented higher rates of the primary composite end point (myocardial infarction, CV death, and stroke) at 1 year compared with those patients without prior stroke or transient ischemic attack. The reduction of the primary composite outcome and total mortality at 1 year with ticagrelor versus clopidogrel was consistent with the overall trial results. The rates of overall PLATO-defined major bleeding events associated with coronary artery bypass graft surgery, as well as major bleeding events, were similar, and intracranial bleeding occurred infrequently in the randomized groups. In light of a favorable clinical net benefit and associated impact on mortality, the results of the present study suggest that treatment with ticagrelor should not be withheld in acute coronary syndrome patients with a history of ischemic stroke or transient ischemic attack for safety concerns if otherwise indicated.Conclusions—Patients with acute coronary syndrome with a prior history of ischemic stroke or transient ischemic attack (TIA) had higher rates of clinical outcomes than patients without prior stroke or TIA. However, the efficacy and bleeding results of ticagrelor in these high-risk patients were consistent with the overall trial population, with a favorable clinical net benefit and associated impact on mortality.7Long-Term Propensity Score–Matched Comparison of Percutaneous Closure of Patent Foramen Ovale With Medical Treatment After Paradoxical EmbolismSummary—The patent foramen ovale (PFO) is a recognized cause of stroke and systemic embolism, the mechanism being a venous clot that passes through the PFO and causes systemic ischemia. For about 20 years, PFOs have been closed percutaneously to prevent such events. The technique has matured and is now quite simple and safe. However, there is no evidence from randomized trials that this technique is safer than a conservative approach consisting of oral anticoagulation, platelet inhibitors, or a combination thereof. The data here represent the longest follow-up of 308 consecutive patients arbitrarily treated with PFO closure or medical therapy. In a propensity score–matched analysis, 103 patients with PFO closure were compared with 103 patients without PFO closure. At the mean follow-up of ≈10 years, a significant clinical event relatable to PFO occurred in 11% of patients with PFO closure and 21% of those without PFO closure (P=0.033). Transient ischemic attacks accounted for most of these events (5% and 14%, respectively). There were no complications with clinical sequelae in the PFO closure group. These data confirm other studies that PFO closure is safe; no late complications were found. The prevention of systemic ischemic events (particularly transient ischemic attacks) appears to be slightly superior to medical treatment.Conclusions—In this long-term observational, propensity score–matched study, percutaneous PFO closure was more effective than medical treatment for the secondary prevention of recurrent cerebrovascular events among patients with PFO-related transient ischemic attack or stroke.8Downregulation of TMEM16A Calcium-Activated Chloride Channel Contributes to Cerebrovascular Remodeling During Hypertension by Promoting Basilar Smooth Muscle Cell ProliferationSummary—During hypertension, cerebral arterioles undergo remodeling of the vascular walls, which contributes to the increased risk for stroke. Accumulating evidence suggests that chloride channels play an important role in regulation of cell cycle transition and cell proliferation and that the upregulation of volume-regulated chloride channel is involved in hypertension-induced cerebrovascular remodeling. Recently, TMEM16A was proposed to be the molecular candidate of the calcium-activated chloride channel (CaCC). TMEM16A has been found to be abundantly expressed and to mediate the calcium-activated chloride current in several types of vascular smooth muscle cells. However, the molecular identity of CaCC and its functions in cerebrovascular smooth muscle cells remain enigmatic. In present study, we demonstrate that TMEM16A is responsible for the CaCC in rat basilar smooth muscle cells. The activity of CaCC in basilar smooth muscle cells is remarkably reduced in hypertensive rats. Upregulation of CaMKII activity and downregulation of TMEM16A expression contribute to the attenuation of CaCC in hypertension. In addition, TMEM16A negatively regulates cell proliferation and cell cycle transition from the G0/G1 phase to the S phase through modifying cyclin D1 and cyclin E expression. These results provide evidence that the reduction of CaCC activity is an important contributor to hypertension-induced vascular smooth muscle cell proliferation and cerebrovascular remodeling, indicating that restoration of the TMEM16A CaCC activity could exert beneficial effects on hypertension-associated cardiovascular diseases such as stroke.Conclusions—TMEM16A CaCC is a negative regulator of cell proliferation. Downregulation of CaCC may play an important role in hypertension-induced cerebrovascular remodeling, suggesting that modification of the activity of CaCC may be a novel therapeutic strategy for hypertension-associated cardiovascular diseases such as stroke.9Migraine Mutations Increase Stroke Vulnerability by Facilitating Ischemic DepolarizationsSummary—Our study establishes a mechanism that links migraine and stroke, 2 highly prevalent and debilitating diseases. Migraine is a well-recognized stroke risk factor. Although its prevalence is on par with other stroke risk factors such as diabetes mellitus and hypertension, there has been little insight into the mechanism of the migraine-stroke association. Here, we present compelling evidence indicating that glutamatergic hyperexcitability associated with migraine mutations renders the brain more susceptible to ischemic depolarizations. As a result, the minimum critical level of blood flow required for tissue survival (ie, viability threshold) is elevated and infarction ensues, even in mildly ischemic tissues. This represents a paradigm shift in the search for a mechanism for increased stroke risk in migraineurs and differs radically from those previously postulated on the basis of clinical data alone. Our conclusions are based on optical and MRI and electrophysiological recordings in transgenic mouse models for familial hemiplegic migraine type 1, a monogenic migraine syndrome (mutations in Cav2.1 channels) that has been a model for common but genetically complex forms of migraine based on shared clinical features, glutamatergic mechanisms, and elevated stroke risk. Clinical implications include a shorter therapeutic window for acute stroke interventions in migraineurs because of accelerated loss of potentially salvageable penumbra. Furthermore, migraine prophylaxis may reduce stroke risk by suppressing cerebral hyperexcitability, and antithrombotic prophylaxis may be indicated in susceptible migraineurs because they are more likely to have infarcts if and when they develop cerebral ischemic events.Conclusions—We propose that enhanced susceptibility to ischemic depolarizations akin to spreading depression predisposes migraineurs to infarction during mild ischemic events, thereby increasing the stroke risk.10Matrix Metalloproteinase-10 Effectively Reduces Infarct Size in Experimental Stroke by Enhancing Fibrinolysis via a Thrombin-Activatable Fibrinolysis Inhibitor–Mediated MechanismSummary—The majority of strokes, the third leading cause of death worldwide, are ischemic in nature. It is estimated that 1 of every 16 deaths is due to stroke, ranking as the No. 1 cause of adult disability with an estimated cost of $74 billion in 2010. With an aging population, these numbers are likely to rise. Intravenous fibrinolysis with recombinant tissue plasminogen activator (tPA) remains the only Food and Drug Administration–approved treatment for stroke patients presenting within 3 hours after onset, which can be extended to 4.5 hours in selected patients. Recombinant tPA, although effective in reducing disability, does not improve mortality. Indeed, most stroke centers use recombinant tPA in only ≈5% of stroke patients. The major adverse effect after recombinant tPA administration is intracerebral hemorrhage, seen in ≈6% to 7% of cases and thus remaining an important clinical issue. Because of the potential side effects of recombinant tPA, efforts are being made to improve recanalization after stroke by using new fibrinolytics or mechanical revascularization therapies. Fibrinolysis and matrix metalloproteinase–mediated proteolysis act in concert to degrade the occlusive fibrin clot. We have demonstrated that matrix metalloproteinase-10 reduces infarct size and favors fibrinolysis through a thrombin-activatable fibrinolysis inhibitor–mediated mechanism in an experimental stroke model in mice, with much lower effect on bleeding than tPA. This novel thrombolytic strategy can open new perspectives for the treatment of stroke, likely reducing the impact of this enormous economic and social burden provided that it can be translated to humans.Conclusions—A novel profibrinolytic role for MMP-10 in experimental ischemic stroke is described, opening new pathways for innovative fibrinolytic strategies in arterial thrombosis.11Stroke in Patients With Type 2 Diabetes Mellitus, Chronic Kidney Disease, and Anemia Treated With Darbepoetin Alfa: The Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) ExperienceSummary—Although anemia has been associated with higher mortality and morbidity in subjects with diabetes mellitus and nondialysis chronic kidney disease, treatments with erythropoiesis-stimulating agents have not led to improvements in prognosis. In the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT), a concerning increase in the risk of darbepoetin alfa–related stroke was observed. We examined the role of baseline predictors and postrandomization factors that might explain this heightened risk of stroke with darbepoetin alfa. We found that in this cohort of patients with type 2 diabetes mellitus, nondialysis chronic kidney disease, and anemia, the risk of stroke related to darbepoetin alfa did not appear to be associated with any baseline characteristic. Despite extensive sensitivity analyses, this risk did not seem to be mediated by postrandomization factors previously implicated as mechanisms of erythropoiesis-stimulating agent–related adverse outcomes, including increase in hemoglobin level, blood pressure, or platelet number, and was not related to dose of darbepoetin alfa. Therefore, clinicians cannot rely on monitoring these readily available follow-up parameters to mitigate the risk of darbepoetin alfa–related stroke.Conclusions—The 2-fold increase in stroke with darbepoetin alfa in TREAT could not be attributed to any baseline characteristic or to postrandomization blood pressure, hemoglobin, platelet count, or dose of treatment. These readily identifiable factors could not be used to mitigate the risk of darbepoetin alfa–related stroke.12Anticoagulation With the Oral Direct Thrombin Inhibitor Dabigatran Does Not Enlarge Hematoma Volume in Experimental Intracerebral HemorrhageSummary—The direct thrombin inhibitor dabigatran was recently approved for long-term prophylaxis of thrombembolic events in patients with atrial fibrillation. For this indication, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial revealed a favorable benefit–risk profile for dabigatran compared with that of the gold standard, warfarin. Intracerebral hemorrhage (ICH) is the most feared complication of long-term anticoagulation. Whereas warfarin pretreatment leads to largely increased hematoma volumes and higher mortality rates compared to those of ICH occurring in nonanticoagulated patients, no such data are available for dabigatran anticoagulation. In 2 animal models of ICH, we found no differences in terms of hematoma volume between dabigatran-treated mice and controls, whereas warfarin anticoagulation dramatically worsened ICH volume. On a molecular level, warfarin vastly reduced activity levels of coagulation factors II, VII, IX, and X, but dabigatran reversibly inhibited the active site of factor II only, still allowing sufficient coagulation induction to prevent extensive hematoma enlargement. If confirmed in humans, our findings may represent a significant safety advantage of dabigatran anticoagulation over that of warfarin. Further study is warranted to determine if rapid anticoagulation reversal (eg, by means of prothrombin complex concentrates) is not necessary for ICH occurring during dabigatran treatment.Conclusions—In contrast with warfarin, pretreatment with dabigatran did not increase hematoma volume in 2 different experimental models of ICH. In terms of safety, this observation may represent a potential advantage of anticoagulation with dabigatran over warfarin.13Global Variation in the Relative Burden of Stroke and Ischemic Heart DiseaseSummary—Stroke and ischemic heart disease account for a substantial and growing share of overall mortality and disease burden worldwide. However, despite having overlapping risk factors and disease mechanisms, there may be significant variation in the relative burden of disease from stroke compared with ischemic heart disease worldwide. In the present study, we used data from the World Health Organization Burden of Disease Program to develop a comprehensive overview of the geographic patterns of variation in burdens of stroke and heart disease. We found that there is substantial global variation in the relative burden of stroke versus ischemic heart disease; mortality and disease burdens from stroke and ischemic heart disease do not track uniformly with each other. There was disproportionately greater stroke burden in China, Africa, and South America, whereas ischemic heart disease burden was greater in the Middle East, North America, Australia, and much of Europe. Lower-income countries have a higher relative stroke burden overall, which may be related in part to associations with vascular risk factor profiles. These data suggest that a better understanding of the reasons for this variation may be helpful to develop targeted national interventions.Conclusions—There is substantial global variation in the relative burden of stroke compared with ischemic heart disease. The disproportionate burden from stroke for many lower-income countries suggests that distinct interventions may be required.14Cost-Effectiveness of Dabigatran for Stroke Prophylaxis in Atrial FibrillationSummary—Each year, in the United States alone, atrial fibrillation causes >50 000 strokes and $12 billion in medical expenditure. Thus, safe and cost-effective stroke prevention is critical to the atrial fibrillation population. Dabigatran etexilate was developed with the ho